US7825112B2 - 2-carbamide-4-phenylthiazole derivatives, preparation thereof and therapeutic use thereof - Google Patents

2-carbamide-4-phenylthiazole derivatives, preparation thereof and therapeutic use thereof Download PDF

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US7825112B2
US7825112B2 US12/146,898 US14689808A US7825112B2 US 7825112 B2 US7825112 B2 US 7825112B2 US 14689808 A US14689808 A US 14689808A US 7825112 B2 US7825112 B2 US 7825112B2
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thiazol
methoxyphenyl
piperazine
amide
alkyl
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Pierre Casellas
Daniel Floutard
Pierre Fraisse
Stephane HOURCADE
Samir Jegham
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Sanofi Aventis France
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention relates to 2-carbamide-4-phenylthiazole derivatives, to the preparation thereof and to the therapeutic application thereof.
  • R 7 is selected from the group constituted by —(C 1 -C 8 )alkyl-COO—(C 1 -C 8 )alkyl, —CO—(C 1 -C 8 )alkyl in which the alkyl is substituted with at least one halogen atom, —(C 3 -C 10 )cycloalkyl, phenyl, —COO—(C 3 -C 10 )cycloalkyl, —SO 2 —(C 1 -C 8 )alkyl in which the alkyl group is substituted with at least one halogen atom, —SO 2 -phenyl in which the phenyl is substituted with at least one —O—(C 1 -C 8 )alkyl group, —SO 2 -heteroaryl in which the heteroaryl is a pyrazole, an isoxazole or an imidazole and in which it is independently substituted with at least one group selected from halogen or
  • R 7 is as defined above
  • R 7 is as defined above
  • a preferred halogen is a fluorine.
  • the compounds of formula (I) may contain one or more asymmetrical carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. Said enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, are encompassed by the invention.
  • the compounds of formula (I) may exist as bases or addition salts with the acids. Said addition salts are encompassed by the invention.
  • Said salts are advantageously prepared with pharmaceutically acceptable acids, but the invention also encompasses salts of other acids used, for example, in purifying or isolating compounds of formula (I).
  • the compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent.
  • the invention also encompasses such hydrates and solvates.
  • R 1 , R 2 , R 3 and Y are as defined above.
  • the compounds of the invention of formula (I.a) are those in which R 1 is in the 2-position and R 2 is in the 5-position of the phenyl group.
  • R 3 represents a group of formula —(CH 2 ) a -A in which a represents 1, 2, 3 or 4, and A is selected from the group constituted by:
  • R 7 , R 1 , R 2 , Y and p are as defined above.
  • the compounds of the invention which may be cited include a second group of compounds of general formula (I) or (I.a) in which R 3 represents a group of formula —CO(CH 2 ) b -A in which b represents 0, 1, 2, 3 or 4, and A is selected from the group constituted by:
  • R 7 , R 1 , R 2 , Y and p are as defined above.
  • the compounds of the invention cited above in the first group and in the second group which may be cited include a sub-group of compounds wherein A is selected from the group constituted by:
  • R 1 , R 2 , Y and p are as defined above.
  • the compounds of the invention which may be cited include a third group of compounds of general formula (I) or (I.a) wherein R 3 represents a group —B wherein B is selected from the group constituted by:
  • R 7 , R 1 , R 2 , Y and p are as defined above.
  • R 7 is selected from the group constituted by —(C 1 -C 8 )alkyl-COO—(C 1 -C 8 )alkyl, —CO—(C 1 -C 8 )alkyl in which the alkyl is substituted with at least one halogen atom, —(C 3 -C 10 )cycloalkyl, phenyl, —SO 2 —(C 1 -C 8 )alkyl in which the alkyl is substituted with at least one halogen atom, —SO 2 -phenyl in which the phenyl is substituted with at least one —O—(C 1 -C 8 )alkyl group, —SO 2 -heteroaryl in which the heteroaryl is a pyrazole or an isoxazole or an imidazole and in which it is independently substituted with at least one group selected from
  • the compounds of the invention include a fourth group of compounds which may be cited of general formula (I) or (I.a) wherein R 3 represents a group of formula —(CH 2 ) a —C in which a represents 1, 2, 3 or 4, and C is selected from the group constituted by:
  • R 8 , R 9 , Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R 1 , R 2 , Y and p are as defined above.
  • the compounds of the invention include a fifth group of compounds which may be cited of general formula (I) or (I.a) wherein R 3 represents a group of formula —CO(CH 2 ) b —C in which b represents 0, 1, 2, 3 or 4, and C is selected from the group constituted by:
  • R 8 , R 9 , Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R 1 , R 2 , Y and p are as defined above.
  • the compounds of the invention cited in the fourth group and in the fifth group include a first sub-group of compounds which may be cited wherein C is selected from the group constituted by:
  • R 9 , Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R 1 , R 2 , Y and p are as defined above.
  • R 8 , Ra, Rb, Rc, Rd, R 1 , R 2 , Y and p are as defined above.
  • the compounds of the invention include a sixth group of compounds which may be cited of general formula (I) or (I.a) in which R 3 represents a group -D wherein D is selected from the group constituted by:
  • R 8 , R 9 , Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R 1 , R 2 , Y and p are as defined above.
  • R 8 is a hydrogen atom or a (C 1 -C 8 )alkyl group.
  • protection group Gp means a group which can, on the one hand, protect a reactive function, such as a hydroxyl group or an amine group during a synthesis and, on the other, can regenerate the intact reactive function at the end of synthesis. Examples of protective groups and methods for protection and deprotection are given in “Protective Groups in Organic Synthesis”, Green et al., 2 nd Edition (John Wiley & Sons, Inc., New York).
  • parting group X as used below means a group which can easily be cleaved from a molecule by breaking a heterolytic bond, with departure of an electron pair. Said group may thus be readily replaced by another group during a substitution reaction, for example.
  • Said parting groups are, for example, halogens or an activated hydroxyl group such as mesyl (methanesulphonyl), tosyl (toluenesulphonyl), triflate, acetate, etc. Examples of parting groups and references to their preparation are given in “Advances in Organic Chemistry”, J. March, 3 rd Edition, Wiley Interscience, p. 310-316.
  • R 1 , R 2 or R 3 precursor as used below means a substituent R′ 1 , R′ 2 or R′ 3 which may be transformed into R 1 , R 2 and R 3 by one or more chemical reactions.
  • group Z means a leaving group of a functional derivative of a carboxylic acid such as an acid chloride, a mixed or symmetrical anhydride, or the appropriately activated acid, for example benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (BOP), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU).
  • BOP benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate
  • HBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate
  • TBTU O-benz
  • R 11 , R 12 and/or R′ 3 represent a group containing an amine or hydroxyl function
  • said functions may be protected in an intermediate manner: an amine function may be protected by an alkanoyl, benzyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc) group, for example; a hydroxyl function may be protected in the ether or ester form, for example.
  • the compounds of the invention may be prepared using various methods described in the present patent application.
  • the present invention concerns processes for preparing products of formula (I) and the intermediate products thereof.
  • the compounds of formula (I) of the invention may be prepared in accordance with the following general scheme 1.
  • the compounds of the invention are obtained by coupling an aminothiazole derivative of formula (II) wherein R 1 , R 2 , Y are as defined above with an amine derivative of formula (III) in which R′ 3 represents a precursor group of R 3 or a group R 3 as defined above and p is as defined above.
  • aminothiazole derivatives of formula (II) may be obtained using the methods described in patent application WO2004/096798.
  • the coupling agent may be selected from those which are known to the skilled person, for example phosgene, di-(N-succinimidyl)carbonate, 1,1′-carbonyl-diimidazole, using methods described in the “Encyclopedia of Reagents for Organic Synthesis”, L. A. Paquette, volume 2, p 1006; volume 4, p 2304; volume 6, p 4107.
  • the reaction may be carried out in various solvents, for example dichloromethane, dimethylformamide, toluene, in the presence of a base such as triethylamine or K 2 CO 3 , at a temperature of 0° C. to 100° C.
  • a base such as triethylamine or K 2 CO 3
  • aminated derivatives of formula (III) are known or can be prepared using the methods described in particular in the document WO 87/01706 or using the methods described below.
  • Groups A′ and C′ below respectively represent a precursor group of group A or C, or a group A or C as defined above.
  • the compounds of formula (IV) are commercially available or may be synthesized from commercially available compounds using methods which are known to the skilled person.
  • the compounds of formula (IV), wherein R′ 3 represents a precursor group of the group R 3 in which R 3 represents a —CO(CH 2 ) b -A or —CO(CH 2 ) b —C group may also be obtained using scheme 2 below:
  • a piperazine or a mono-protected homo-piperazine reacts with a compound of formula (V.1) or (V.2) in which Z represents a leaving group, or a group derived from activation of a carboxylic acid function, to respectively give the compound of formula (IV.2) or (IV.5) by acylation or peptide type coupling in the presence of a base such as K 2 CO 3 , triethylamine, diisopropylthylamine or caesium carbonate, optionally in the presence of a coupling reagent such as BOP, TBTU or CDI, in a solvent such as THF, acetonitrile or DMF at temperatures of 0° C. to 150° C.
  • a piperazine or a mono-protected homo-piperazine reacts with an aldehyde of formula (VI.1) or (VI.2) to respectively give the compound of formula (IV.1) or (IV.4) under reductive amination reaction conditions in the presence of a reducing agent such as NaHB(OAc) 3 or NaBH 3 CN in a solvent such as 1,2-dichloroethane, dichloromethane, methanol or THF at temperatures of 0° C. to 70° C.
  • the compounds of formula (IV.1) and (IV.4) may be synthesized by a substitution reaction using the process illustrated in scheme 4 below:
  • a piperazine or a mono-protected homo-piperazine reacts with a compound of formula (VII.1) or (VII.2) in which X represents a leaving group to respectively produce the compound of formula (IV.1) or (IV.4).
  • the reaction is carried out without solvent or in a solvent such as tetrahydrofuran, dimethylformamide, toluene or acetonitrile in the presence or absence of a base such as triethylamine or K 2 CO 3 at temperatures from ambient temperature to 200° C. for a period of 1 to 24 hours.
  • ketones B′ and D′ used are commercially available or may be synthesized using the methods described in Organic Process Research & Development, 2004, 8, 939 ; Synthesis, 1989, 10, 767.
  • the compounds of formula (I) may also be prepared using scheme 6 below.
  • the compound of formula (VIII) is then deprotected to produce the compound of formula (IX), using methods which are known to the skilled person, which is reacted with a compound of formula (V.1), (V.2), (VI.1), (VI.2), (VII.1) or (VII.2), or with a ketone of formula B′ or of formula D′ as defined above.
  • This reaction is carried out in accordance with the processes described above for synthesizing intermediates of formula (IV).
  • the compounds were analyzed by coupled HPLC-UV-MS (liquid chromatography-UV detection-mass spectrometry).
  • the apparatus used, sold by Agilent was composed of a HP1100 chromatograph provided with an Agilent diode array detector and a MSD Quadripolar mass spectrometer.
  • the unrefined product obtained in step 1.1 was dissolved in 75 ml of toluene. 12.16 g of benzylpiperazine were added, the reaction medium was sealed off and heated for 5 hours at 150° C. After returning to AT, the medium was diluted in an ether/pentane (1/1) mixture, washed twice with a saturated NaHCO 3 solution, twice in water then with a saturated NaCl solution. After drying over MgSO 4 and evaporating, the unrefined product was purified by silica gel flash chromatography to produce 5.73 g of the expected solid.
  • a solution of 4.0 g of the compound obtained in step 1.2 in 30 ml of methanol was hydrogenated in a closed reactor with microwave irradiation at 80° C. for 10 minutes in the presence of 1.7 g of Pd/C, 10% moisture, and 2.02 g of ammonium formate.
  • the medium was filtered then evaporated to produce 2.89 g of a colourless oil.
  • This compound could be obtained using the process described in preparation 1.4 between 4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-amine and 1-(tetrahydro-2H-pyran-4-yl)piperazine described in J. Med. Chem.; EN; 47; 11; 2004; 2833-2838.
  • Synthesis may be carried out by another method:
  • the beige powder obtained was purified by silica gel flash chromatography to produce 1.42 g of the expected compound in the form of a white solid.
  • This compound was synthesized starting from the compound described in preparation 1.5 and from ethyl 2-bromoacetate using an identical process to that described in preparation 4.
  • This compound was synthesized from the compound described in preparation 9.1 using an identical process to that described in preparation 5.
  • 0.1 g of TBTU, 0.02 g of HOBt then 0.08 ml of DIPEA were added to a solution of 0.1 g of the compound described in step 9.2 in 1 ml of DCM. After stirring for 2 hours at AT, ammonia was bubbled into the solution for 2 hours. The reaction medium was filtered, the filtrate was washed with a saturated NaHCO 3 solution then with a saturated NaCl solution. After drying over MgSO 4 , the organic phase was concentrated to produce 0.09 g of unrefined product. The unrefined product was purified by silica gel flash chromatography to produce 0.052 g of the expected compound in the form of a white solid.
  • the compounds according to the invention were used in pharmacological tests to determine the modulator effect thereof on the activity of chemokine receptors.
  • Chemokines are low molecular weight proteins which belong to the category of pro-inflammatory cytokines and are involved in the chemotactism of leukocytes and endothelial cells. Chemokines control a number of biological processes and are associated with inflammatory disorders appearing during stress conditions, with wounds or with infections; modulation of the effects of chemokines allows pathologies such as asthma, arthritis, allergies, auto-immune diseases, atherosclerosis or angiogenesis to be prevented or treated (C. D. Paavola et al., J. Biol. Chem., 1998, 273, (50), 33157-33165).
  • Chemokines include hMCP-1 (human monocyte chemotactic protein) which belongs to the CC chemokine group and is a natural agonist of the CCR2b receptor.
  • the inhibiting activity of the compounds according to the invention was measured on cells expressing the human CCR2b receptor.
  • the concentration of natural hMCP-1 agonist which inhibited 50% (Cl 50 ) of the activity of the CCR2b receptor was 0.57 nM.
  • the compounds according to the invention had a Cl 50 which was generally in the range 0.1 ⁇ M to 0.1 nM, preferably in the range 100 nM to 0.1 nM.
  • Recombinant human MCP-1) (final concentration of compound: 10 ⁇ 5 M), and 50 ⁇ l of iodinated MCP-1 ([ 125 l ]-MCP-1 human recombinant Bolton+Hunter labelled (Amersham)) at 0.3 nM in distilled water (final concentration of iodinated MCP-1: 0.1 nM), and 50 ⁇ l of CHO-K1-CCR2B cells (obtained from Euroscreen Brussels, Belgium) at 6 ⁇ 10 5 cells/ml (final concentration in the reaction buffer: 3 ⁇ 10 5 cells/wells).
  • the filters were saturated beforehand with 100 ⁇ l of PEI at a final concentration of 0.0125% in PBS, for 72 h at 4° C., and the PEI was removed by filtration. The content of the wells was filtered and washed twice with the reaction buffer, and the filters were left to dry overnight. The following day, 20 ⁇ l/well of “Wallac Optiphase Super Mix” scintillant were dispensed. The filters were impregnated for 1 to 2 h and then counted with Trilux Iodine 125 for 1 min.
  • Reaction buffer PBS buffer, 50 nM Hepes, 1 mM CaCl 2 , 5 mM MgCl 2 , 0.5% fatty acid-free BSA, adjusted to pH 7.4.
  • compound No 9 had a Cl 50 of 4 nM
  • compound No 10 had a Cl 50 of 53 nM
  • compound No 22 had a Cl 50 of 4 nM
  • compound No 40 had a Cl 50 of 82 nM
  • compound No 41 had a Cl 50 of 39 nM
  • compound No 33 had a Cl 50 of 20 nM
  • compound No 11 had a Cl 50 of 20 nM
  • compound No 23 had a Cl 50 of 8 nM
  • compound No 29 had a Cl 50 of 50 nM
  • compound No 45 had a Cl 50 of 73 nM.
  • the compounds according to the invention can thus be used to prepare drugs, in particular drugs which are antagonists to the effect of chemokines.
  • the present invention pertains to drugs which comprise a compound of formula (I) or an addition salt thereof with a pharmaceutically acceptable acid, or a hydrate or a solvate.
  • Said drugs can be used in therapy, in particular in the prevention and treatment of various pathologies such as:
  • the present invention concerns pharmaceutical compositions comprising a compound according to the invention as the active principle.
  • Said pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or a solvate of said compound, and at least one pharmaceutically acceptable excipient.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active principle of formula (I) above, or any salt, solvate or hydrate thereof, may be administered in a unitary administration form, mixed with conventional pharmaceutical excipients, to animals and humans for prophylaxis or to treat the problems or diseases mentioned above.
  • Suitable unitary administration forms include oral forms such as tablets, soft or hard gelules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal or inhaled forms of administration, topical, transdermal, subcutaneous, intramuscular or intravenous forms of administration, rectal forms of administration and implants.
  • oral forms such as tablets, soft or hard gelules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal or inhaled forms of administration, topical, transdermal, subcutaneous, intramuscular or intravenous forms of administration, rectal forms of administration and implants.
  • the compounds according to the invention may be used in creams, gels, pomades or lotions.
  • a unitary form of administration of a compound of the invention in the form of a tablet may comprise the following components:
  • the dose of active principle administered per day may be from 0.1 to 1000 mg/kg, in one or more doses.
  • the appropriate dose for each patient is determined by the physician as a function of the mode of administration and the patient's weight and response.
  • the present invention also concerns a method for treating the disorders indicated above, which comprises administering an effective dose of a compound according the invention, or one of its pharmaceutically acceptable salts or hydrates or solvates, to a patient.

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Abstract

The disclosure relates to 2-carbamide-4-phenylthiazole derivatives having the following general formula (I):
Figure US07825112-20101102-C00001
wherein R1, R2, R3, Y and p are as defined in the disclosure. The disclosure also relates to pharmaceutical compositions containing a compound of formula (I), to processes for preparing the compounds of formula (I), and to methods of using the compounds of formula (I).

Description

The invention relates to 2-carbamide-4-phenylthiazole derivatives, to the preparation thereof and to the therapeutic application thereof.
The invention concerns compounds corresponding to formula (I) below:
Figure US07825112-20101102-C00002
wherein:
    • R1 represents a hydrogen atom, a halogen atom, a (C1-C8)alkyl, trifluoro(C1-C4)alkyl, —OH, —O—(C1-C8)alkyl, —O-trifluoro(C1-C8)alkyl, —O—(C1-C8)alkyl-(C3-C10)cycloalkyl, —O—(C3-C10)cycloalkyl, —O—CH2—CH═CH2 or —S—(C1-C4)alkyl group;
    • R2 represents a hydrogen atom, a halogen atom, an —OH, (C1-C8)alkyl, trifluoro(C1-C4)alkyl, perfluoro(C1-C4)alkyl, (C3-C10)cycloalkyl, —O—(C1-C8)alkyl, —O—(C1-C8)alkyl(C3-C10)cycloalkyl, —O—(C3-C10)cycloalkyl, —O—CH2—CH═CH2 or —(C1-C8)alkyl(C3-C8)cycloalkyl group;
    • Y represents a hydrogen atom or a halogen atom;
    • p represents 2 or 3;
    • R3 represents:
  • a1) a group of formula —(CH2)a-A
    in which a represents 1, 2, 3 or 4, and A is selected from the group constituted by:
Figure US07825112-20101102-C00003
in which R7 is selected from the group constituted by —(C1-C8)alkyl-COO—(C1-C8)alkyl, —CO—(C1-C8)alkyl in which the alkyl is substituted with at least one halogen atom, —(C3-C10)cycloalkyl, phenyl, —COO—(C3-C10)cycloalkyl, —SO2—(C1-C8)alkyl in which the alkyl group is substituted with at least one halogen atom, —SO2-phenyl in which the phenyl is substituted with at least one —O—(C1-C8)alkyl group, —SO2-heteroaryl in which the heteroaryl is a pyrazole, an isoxazole or an imidazole and in which it is independently substituted with at least one group selected from halogen or —(C1-C8)alkyl, —SO2—N((C1-C8)alkyl)2, —SO2—OH, —SO2—(C3-C10)cycloalkyl, —CO—NH((C1-C8)alkyl), —(C1-C8)alkyl-CN, —(C1-C8)alkylimidazole, —(C1-C8)alkyl-COOH, —(C1-C8)alkyl-COO−M+, —(C1-C8)alkyl-OH, —(C1-C8)alkyltetrazole, —(C1-C8)alkyl-CO—NH2, —(C1-C8)alkyl-CO—NH((C1-C8)alkyl), —(C1-C8)alkyl-CO—NH((C3-C10)cycloalkyl), —(C1-C8)alkyl-CO—N((C1-C8)alkyl)((C3-C10)cycloalkyl), —(C1-C8)alkyl-CO—N((C1-C8)alkyl)2, —(C1-C8)alkyl-CO—N((C3-C10)cycloalkyl)2, in which M+ is an alkali metal cation selected from Li+, Na+ and K+, and when two alkyl or cycloalkyl substituents are bonded to the nitrogen atom, they may be independently identical or different;
  • a2) a group of formula —CO(CH2)b-A
    in which b represents 0, 1, 2, 3 or 4, and A is selected from the group constituted by:
Figure US07825112-20101102-C00004
in which R7 is as defined above;
  • a3) a group —B
    in which B is selected from the group constituted by:
Figure US07825112-20101102-C00005
in which R7 is as defined above;
  • a4) a group of formula —(CH2)a—C
    in which a represents 1, 2, 3 or 4, and C is selected from the group constituted by:
Figure US07825112-20101102-C00006
in which:
    • R8 is selected from the group constituted by a hydrogen atom, a (C1-C8)alkyl, —(C1-C8)alkyl-COO—(C1-C8)alkyl, —CO—(C1-C8)alkyl group in which the alkyl is optionally substituted with at least one halogen atom, —(C3-C10)cycloalkyl, phenyl, —COO—(C3-C10)cycloalkyl, —SO2—(C1-C8)alkyl in which the alkyl is optionally substituted with at least one halogen atom, —SO2-phenyl in which the phenyl is optionally substituted with at least one —O—(C1-C8)alkyl group, —SO2-heteroaryl in which the heteroaryl is a pyrazole, an isoxazole or an imidazole and in which it is optionally independently substituted with at least one group selected from halogen or —(C1-C8)alkyl, —SO2—N((C1-C8)alkyl)2, —SO2—OH, —SO2—(C3-C10)cycloalkyl, —CO—NH((C1-C8)alkyl), —(C1-C8)alkyl-CN, —(C1-C8)alkylimidazole, —(C1-C8)alkyl-COOH, —(C1-C8)alkyl-COO−M+, —(C1-C8)alkyl-OH, —(C1-C8)alkyltetrazole, —(C1-C8)alkyl-CO—NH2, —(C1-C8)alkyl-CO—NH((C1-C8)alkyl), —(C1-C8)alkyl-CO—NH((C3-C10)cycloalkyl), —(C1-C8)alkyl-CO—N((C1-C8)alkyl)((C3-C10)cycloalkyl), —(C1-C8)alkyl-CO—N((C1-C8)alkyl)2, —(C1-C8)alkyl-CO—N((C3-C10)cycloalkyl)2, in which M+ is an alkali metal cation selected from Li+, Na+ and K+, and when two alkyl or cycloalkyl substituents are bonded to a nitrogen atom, they may be independently identical or different;
    • R9 is selected from the group constituted by: hydroxyl, O—(C1-C8)alkyl, —O-trifluoro(C1-C8)alkyl, —O—(C1-C8)alkyl(C3-C10)cycloalkyl, —O—(C3-C10)cycloalkyl;
    • Ra, Rb, Rc and Rd are independently a hydrogen atom or a methyl group, given that at least one of Ra, Rb, Rc and Rd is a methyl group;
    • Re, Rf, Rg and Rh are independently a hydrogen atom or a methyl group;
  • a5) a group of formula —CO(CH2)b—C
in which b represents 0, 1, 2, 3 or 4, and C is selected from the group constituted by:
Figure US07825112-20101102-C00007
in which:
    • R8, R9, Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are as defined above;
  • a6) a group -D
    wherein D is selected from the group constituted by:
Figure US07825112-20101102-C00008
in which:
    • R8, R9, Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh are as defined above; constituted as a base or an addition salt with an acid, as well as constituted as hydrates or solvates.
A preferred halogen is a fluorine.
The compounds of formula (I) may contain one or more asymmetrical carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. Said enantiomers, diastereoisomers and mixtures thereof, including racemic mixtures, are encompassed by the invention.
The compounds of formula (I) may exist as bases or addition salts with the acids. Said addition salts are encompassed by the invention.
Said salts are advantageously prepared with pharmaceutically acceptable acids, but the invention also encompasses salts of other acids used, for example, in purifying or isolating compounds of formula (I).
The compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. The invention also encompasses such hydrates and solvates.
The following definitions are used in the present invention:
    • Ct-z, in which t and z may take values of 1 to 10, means a carbonaceous chain which may contain t to z carbon atoms, for example C1-3 means a carbonaceous chain which may contain 1 to 3 carbon atoms;
    • a halogen atom means, for example, a fluorine, a chlorine, a bromine or an iodine;
    • an alkyl group: a linear or branched, saturated aliphatic group optionally substituted with a halogen atom. Examples which may be cited are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, 2-fluoroethyl groups, etc;
    • a cycloalkyl group: a cyclic alkyl group. Examples which may be cited are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups, etc;
    • a perfluoroalkyl group: an alkyl radical, as defined above, wherein all of the carbon atoms have been substituted with fluorine atoms.
The compounds encompassed by the subject-matter of the invention which may be cited include those of formula (I.a) below:
Figure US07825112-20101102-C00009
in which R1, R2, R3 and Y are as defined above.
The compounds of the invention of formula (I.a) are those in which R1 is in the 2-position and R2 is in the 5-position of the phenyl group.
The compounds of the invention which may be cited include those in which:
    • R1 represents an —O—(C1-C8)alkyl group; and/or
    • R2 represents a (C1-C8)alkyl, (C3-C10)cycloalkyl, perfluoro(C1-C4)alkyl or —O—(C1-C8)alkyl group.
A sub-group of these compounds which may be cited includes those in which:
    • R1 represents an —O—(C1-C8)alkyl group; and/or
    • R2 represents a (C1-C8)alkyl, (C3-C10)cycloalkyl or —O—(C1-C8)alkyl group.
The compounds of the invention which may be cited are included in a first group of compounds of formula (I) or (I.a) wherein R3 represents a group of formula —(CH2)a-A in which a represents 1, 2, 3 or 4, and A is selected from the group constituted by:
Figure US07825112-20101102-C00010
in which R7, R1, R2, Y and p are as defined above.
The compounds of the invention which may be cited include a second group of compounds of general formula (I) or (I.a) in which R3 represents a group of formula —CO(CH2)b-A in which b represents 0, 1, 2, 3 or 4, and A is selected from the group constituted by:
Figure US07825112-20101102-C00011
in which R7, R1, R2, Y and p are as defined above.
The compounds of the invention cited above in the first group and in the second group which may be cited include a sub-group of compounds wherein A is selected from the group constituted by:
Figure US07825112-20101102-C00012
in which R1, R2, Y and p are as defined above.
The compounds of the invention which may be cited include a third group of compounds of general formula (I) or (I.a) wherein R3 represents a group —B wherein B is selected from the group constituted by:
Figure US07825112-20101102-C00013
in which R7, R1, R2, Y and p are as defined above.
Included in the compounds of the invention cited above, a first sub-group of compounds may be cited wherein R7 is selected from the group constituted by —(C1-C8)alkyl-COO—(C1-C8)alkyl, —CO—(C1-C8)alkyl in which the alkyl is substituted with at least one halogen atom, —(C3-C10)cycloalkyl, phenyl, —SO2—(C1-C8)alkyl in which the alkyl is substituted with at least one halogen atom, —SO2-phenyl in which the phenyl is substituted with at least one —O—(C1-C8)alkyl group, —SO2-heteroaryl in which the heteroaryl is a pyrazole or an isoxazole or an imidazole and in which it is independently substituted with at least one group selected from halogen or —(C1-C8)alkyl, —SO2—N((C1-C8)alkyl)2, —SO2—OH, —CO—NH((C1-C8)alkyl), —(C1-C8)alkyl-CN, —(C1-C8)alkyl-COOH, —(C1-C8)alkyl-COO−M+, —(C1-C8)alkyl-OH, —(C1-C8)alkyltetrazole, —(C1-C8)alkyl-CO—NH2, in which M+ is an alkali metal cation selected from Li+, Na+ and K+, and when two alkyl or cycloalkyl substituents are bonded to a nitrogen atom, they may be independently identical or different, as well as a second sub-group of compounds wherein R7 represents —SO2—(C3-C10)cycloalkyl.
Included in the compounds of formula (I) of the invention cited above are the following particular compounds:
  • 4-((S)-1-cyclopropylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-(1-isopropylcarbamoylpiperidin-3-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-(1-cyclopropanesulphonylpiperidin-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • the ethyl ester of 3-((R)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)propionic acid;
  • 3-((R)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)propionic acid;
  • the ethyl ester of 4-((R)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)butyric acid;
  • 4-((R)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)butyric acid;
  • the ethyl ester of 5-((R)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)pentanoic acid;
  • 5-((R)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)pentanoic acid;
  • 4-cyclohexylpiperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide.
More particularly, the following compound can be cited: 4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide.
Included in the compounds of formula (I) of the invention cited above are the following further particular compounds:
  • 4-((S)-1-cyclopropylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-(tetrahydropyran-4-carbonyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-((S)-1-carbamoylmethylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • ((S)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)acetic acid;
  • 4-((S)-1-cyclopropylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)-5-fluorothiazol-2-yl]amide;
  • 4-(tetrahydropyran-4-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • the ethyl ester of ((S)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)acetic acid;
  • 4-[(R)-1-(2-cyanoethyl)piperidin-3-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • the sodium salt of 3-((R)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)propionic acid;
  • 4-[(R)-1-(2-carbamoylethyl)piperidin-3-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-((R)-1-cyclopropylpiperidine-3-carbonyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-((S)-1-cyclopropylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-butyl-2-ethoxyphenyl)thiazol-2-yl]amide;
  • 4-((S)-1-cyclopropylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclopentyl-2-ethoxyphenyl)thiazol-2-yl]amide;
  • 4-((S)-1-cyclopropylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-butyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-((S)-1-cyanomethylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-((R)-1-cyclopropylpiperidin-3-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-(1-cyclopropylpiperidin-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-((S)-1-cyclopropanesulphonylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-((S)-1-phenylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 2-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidine-1-sulphonic acid;
  • 4-[(S)-1-(2-hydroxyethyl)piperidin-3-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-[(S)-1-(2,2,2-trifluoroacetyl)piperidin-3-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)-5-fluorothiazol-2-yl]amide;
  • 4-((S)-1-dimethylsulphamoylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-[(S)-1-(2H-tetrazol-5-ylmethyl)piperidin-3-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-[1-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulphonyl)piperidin-2-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-[1-(1,3-dimethyl-1H-pyrazole-4-sulphonyl)piperidin-2-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-[1-(1,5-dimethyl-1H-pyrazole-4-sulphonyl)piperidin-2-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-[1-(1-methyl-1H-pyrazole-4-sulphonyl)piperidin-2-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-[1-(5-methylisoxazole-4-sulphonyl)piperidin-2-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-[1-(1-methyl-1H-imidazole-4-sulphonyl)piperidin-2-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-(1-dimethylsulphamoylpiperidin-2-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-[1-(2,2,2-trifluoroethanesulphonyl)piperidin-2-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-[1-(4-methoxybenzenesulphonyl)piperidin-2-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclopentyl-2-ethoxyphenyl)thiazol-2-yl]amide;
  • 4-[1-(3,5-dimethylisoxazole-4-sulphonyl)piperidin-2-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-butyl-2-ethoxyphenyl)thiazol-2-yl]amide;
  • 4-[(S)-1-(1-methyl-1H-imidazole-4-sulphonyl)piperidin-3-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-ethoxyphenyl)thiazol-2-yl]amide;
  • 4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclopentyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-butyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(2-methoxy-5-propoxyphenyl)thiazol-2-yl]amide;
  • 4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-propyl-2-methoxyphenyl)thiazol-2-yl]amide;
  • 4-(tetrahydropyran-4-yl)[1,4]diazepane-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide.
The compounds of the invention include a fourth group of compounds which may be cited of general formula (I) or (I.a) wherein R3 represents a group of formula —(CH2)a—C in which a represents 1, 2, 3 or 4, and C is selected from the group constituted by:
Figure US07825112-20101102-C00014
in which R8, R9, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R2, Y and p are as defined above.
The compounds of the invention include a fifth group of compounds which may be cited of general formula (I) or (I.a) wherein R3 represents a group of formula —CO(CH2)b—C in which b represents 0, 1, 2, 3 or 4, and C is selected from the group constituted by:
Figure US07825112-20101102-C00015
in which R8, R9, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R2, Y and p are as defined above.
The compounds of the invention cited in the fourth group and in the fifth group include a first sub-group of compounds which may be cited wherein C is selected from the group constituted by:
Figure US07825112-20101102-C00016
in which R9, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R2, Y and p are as defined above.
The compounds of the invention cited in the fourth group and in the fifth group include a second sub-group of compounds which may be cited wherein C represents:
Figure US07825112-20101102-C00017
in which R8, Ra, Rb, Rc, Rd, R1, R2, Y and p are as defined above.
The compounds of the invention include a sixth group of compounds which may be cited of general formula (I) or (I.a) in which R3 represents a group -D wherein D is selected from the group constituted by:
Figure US07825112-20101102-C00018
in which R8, R9, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, R1, R2, Y and p are as defined above. In this sixth group, a sub-group of compounds may be cited in which R8 is a hydrogen atom or a (C1-C8)alkyl group.
The compounds of formula (I) of the invention cited in the third, fourth and fifth groups and in their sub-groups which may be cited include the following particular compounds:
    • 4-(1,1-dioxohexahydro-1λ6)-thiopyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
    • 4-(4-hydroxycyclohexyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
    • 4-(1,2,2,6,6-pentamethylpiperidin-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
    • 4-(2,2,6,6-tetramethylpiperidin-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
    • 4-(2,2-dimethyltetrahydropyran-4-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
    • 4-(tetrahydrothiopyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide.
Certain intermediates which are of use in preparing compounds of formula (I) may also act as a final product of formula (I), as will become apparent from the examples given below.
In a similar manner, certain compounds of formula (I) of the invention may act as intermediates for use in preparing compounds of formula (I) according to the invention.
The term “protective group Gp” as used below means a group which can, on the one hand, protect a reactive function, such as a hydroxyl group or an amine group during a synthesis and, on the other, can regenerate the intact reactive function at the end of synthesis. Examples of protective groups and methods for protection and deprotection are given in “Protective Groups in Organic Synthesis”, Green et al., 2nd Edition (John Wiley & Sons, Inc., New York).
The term “parting group X” as used below means a group which can easily be cleaved from a molecule by breaking a heterolytic bond, with departure of an electron pair. Said group may thus be readily replaced by another group during a substitution reaction, for example. Said parting groups are, for example, halogens or an activated hydroxyl group such as mesyl (methanesulphonyl), tosyl (toluenesulphonyl), triflate, acetate, etc. Examples of parting groups and references to their preparation are given in “Advances in Organic Chemistry”, J. March, 3rd Edition, Wiley Interscience, p. 310-316.
The term “R1, R2 or R3 precursor” as used below means a substituent R′1, R′2 or R′3 which may be transformed into R1, R2 and R3 by one or more chemical reactions.
The term “group Z” as used below means a leaving group of a functional derivative of a carboxylic acid such as an acid chloride, a mixed or symmetrical anhydride, or the appropriately activated acid, for example benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (BOP), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU).
When one or more substituents R11, R12 and/or R′3 represent a group containing an amine or hydroxyl function, said functions may be protected in an intermediate manner: an amine function may be protected by an alkanoyl, benzyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc) group, for example; a hydroxyl function may be protected in the ether or ester form, for example.
The compounds of the invention may be prepared using various methods described in the present patent application. In a first aspect, the present invention concerns processes for preparing products of formula (I) and the intermediate products thereof.
The compounds of formula (I) of the invention may be prepared in accordance with the following general scheme 1.
Figure US07825112-20101102-C00019
In accordance with scheme 1, the compounds of the invention are obtained by coupling an aminothiazole derivative of formula (II) wherein R1, R2, Y are as defined above with an amine derivative of formula (III) in which R′3 represents a precursor group of R3 or a group R3 as defined above and p is as defined above.
The aminothiazole derivatives of formula (II) may be obtained using the methods described in patent application WO2004/096798.
In scheme 1, the aminothiazole derivative of formula (II) is brought into the presence of a coupling agent for a period of 2 to 16 hours, then with the amine derivative of formula (III) for a period of 0.5 to 4 hours.
The coupling agent may be selected from those which are known to the skilled person, for example phosgene, di-(N-succinimidyl)carbonate, 1,1′-carbonyl-diimidazole, using methods described in the “Encyclopedia of Reagents for Organic Synthesis”, L. A. Paquette, volume 2, p 1006; volume 4, p 2304; volume 6, p 4107.
The reaction may be carried out in various solvents, for example dichloromethane, dimethylformamide, toluene, in the presence of a base such as triethylamine or K2CO3, at a temperature of 0° C. to 100° C.
The aminated derivatives of formula (III) are known or can be prepared using the methods described in particular in the document WO 87/01706 or using the methods described below. Groups A′ and C′ below respectively represent a precursor group of group A or C, or a group A or C as defined above.
The compounds of formula (III), in which R′3 represents a precursor group of R3 or a group R3 as defined above and in which p is as defined above, are obtained from compounds of formula (IV) by deprotecting the nitrogen of the piperazine or the homo-piperazine protected using methods which are known to the skilled person or described in the literature (WO03/104230 and WO03/057145).
By way of example, the following procedure may be followed:
Figure US07825112-20101102-C00020
The compounds of formula (IV) are commercially available or may be synthesized from commercially available compounds using methods which are known to the skilled person. The compounds of formula (IV), wherein R′3 represents a precursor group of the group R3 in which R3 represents a —CO(CH2)b-A or —CO(CH2)b—C group (compounds of formula (IV.2) or (IV.5)), may also be obtained using scheme 2 below:
Figure US07825112-20101102-C00021
In scheme 2, a piperazine or a mono-protected homo-piperazine (Gp=BOC or Gp=benzyl) reacts with a compound of formula (V.1) or (V.2) in which Z represents a leaving group, or a group derived from activation of a carboxylic acid function, to respectively give the compound of formula (IV.2) or (IV.5) by acylation or peptide type coupling in the presence of a base such as K2CO3, triethylamine, diisopropylthylamine or caesium carbonate, optionally in the presence of a coupling reagent such as BOP, TBTU or CDI, in a solvent such as THF, acetonitrile or DMF at temperatures of 0° C. to 150° C.
The compounds of formula (IV), wherein R′3 represents a precursor group of the group R3 in which R3 represents a —(CH2)a-A or —(CH2)a—C group (compounds of formula (IV.1) or (IV.4)), may also be obtained using scheme 3 below:
Figure US07825112-20101102-C00022
In this process, a piperazine or a mono-protected homo-piperazine (Gp=BOC or Gp=benzyl) reacts with an aldehyde of formula (VI.1) or (VI.2) to respectively give the compound of formula (IV.1) or (IV.4) under reductive amination reaction conditions in the presence of a reducing agent such as NaHB(OAc)3 or NaBH3CN in a solvent such as 1,2-dichloroethane, dichloromethane, methanol or THF at temperatures of 0° C. to 70° C. (Synth. Commun., 1998, 28 (10), 1897-1905, J. Org. Chem., 1992, 57 (11), 3218-3225, J. Org. Chem., 1996, 61, 3849-3862, Tetrahedron Lett., 1990, 31, 5595-5598).
Alternatively, the compounds of formula (IV.1) and (IV.4) may be synthesized by a substitution reaction using the process illustrated in scheme 4 below:
Figure US07825112-20101102-C00023
In scheme 4, a piperazine or a mono-protected homo-piperazine (Gp=BOC or Gp=benzyl) reacts with a compound of formula (VII.1) or (VII.2) in which X represents a leaving group to respectively produce the compound of formula (IV.1) or (IV.4). The reaction is carried out without solvent or in a solvent such as tetrahydrofuran, dimethylformamide, toluene or acetonitrile in the presence or absence of a base such as triethylamine or K2CO3 at temperatures from ambient temperature to 200° C. for a period of 1 to 24 hours.
The compounds of formula (IV), wherein R′3 represents a precursor group of the group R3 in which R3 represents a —B or -D group (compounds of formula (IV.3) or (IV.6)), may be prepared by reacting a piperazine or a mono-protected homo-piperazine (Gp=BOC or Gp=benzyl) and a ketone precursor B′ of B or a ketone precursor D′ of D, by a reductive amination reaction in the presence of a reducing agent such as NaHB(OAc)3, NaBH3CN in a solvent such as 1,2-dichloroethane, methanol or dichloromethane, THF at temperatures of 0° C. to 70° C. using the following scheme:
Figure US07825112-20101102-C00024
The ketones B′ and D′ used are commercially available or may be synthesized using the methods described in Organic Process Research & Development, 2004, 8, 939; Synthesis, 1989, 10, 767.
The compounds of formula (I) may also be prepared using scheme 6 below.
Figure US07825112-20101102-C00025
In scheme 6, the aminothiazole derivative of formula (II) as defined above is coupled to a piperazine or a mono-protected homo-piperazine (Gp=BOC or Gp=benzyl) to produce the compound of formula (VIII).
The reaction is carried out under the conditions described above given for scheme 1.
The compound of formula (VIII) is then deprotected to produce the compound of formula (IX), using methods which are known to the skilled person, which is reacted with a compound of formula (V.1), (V.2), (VI.1), (VI.2), (VII.1) or (VII.2), or with a ketone of formula B′ or of formula D′ as defined above. This reaction is carried out in accordance with the processes described above for synthesizing intermediates of formula (IV).
In the general synthesis schemes, when the mode of preparation thereof has not been described, this means that the starting compounds and the reagents are commercially available or have been described in the literature, or they may be prepared using the methods described here or which are known to the skilled person.
The following examples describe the preparation of compounds in accordance with the invention. The numbers of the compounds refer to those given in Table I, which shows the chemical structures of some compounds according to the invention.
In the preparations and examples below:
    • CyHex=a cyclohexyl group;
    • DSC=di-(N-succinimidyl)carbonate;
    • CDI=1,1′-carbonyldiimidazole;
    • DCE=dichloroethane;
    • TBME=tert-butyl methyl ether;
    • AT=ambient temperature;
    • DCM=dichloromethane;
    • DIPEA=diisopropylthylamine;
    • THF=tetrahydrofuran;
    • BOP=benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate;
    • DMF=dimethylformamide;
    • Boc=tert-butyloxycarbonyl;
    • TFA=trifluoroacetic acid;
    • TBTU=2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate;
    • HOBT=hydroxybenzotriazole;
    • BSA=bis(trimethylsilyl)acetamide;
    • EtOAc=ethyl acetate;
    • AcCl=acetyl chloride;
    • MP=Melting Point (in degrees Celsius) measured using a Büchi B545 apparatus with a temperature gradient of 1° C. per minute;
    • MH+=molecular mass of the form of the molecule ionized by a proton.
The compounds were analyzed by coupled HPLC-UV-MS (liquid chromatography-UV detection-mass spectrometry). The apparatus used, sold by Agilent, was composed of a HP1100 chromatograph provided with an Agilent diode array detector and a MSD Quad quadripolar mass spectrometer.
The following analytical conditions were employed:
  • Column; Symmetry C18(50 ×2.1 mm; 3.5 μm )
  • Eluent A: H2O +TFA 0.005% at a pH of 3.15
  • Eluent B: CH3 CN +TFA 0.005%
Gradient:
Time (min) % B
0 0
10 90
15 90
16 0
20 0
Column temperature: 30° C.
Flow rate: 0.4 ml/min
Detection: λ = 220 nm
Where “method B” is indicated in Table 1, the compounds were analyzed by LCMS under the following conditions: YMC Jsphere column (33×2.1 mm, 4 μm, eluent: CH3CN+0.05% TFA: H2O+0.05% TFA, gradient: 5:95 (0 min), then 95:5 (2.5 min), then 95:5 (3 min), flow rate: 1.3 mL/min, temperature: 30° C.
    • rt=retention time.
    • NMR=nuclear magnetic resonance, carried out with a Bruker Avance 200 (200 MHz) spectrometer. The solvent used was deuterated DMSO and the chemical displacements were expressed with respect to TMS. The following abbreviations were used:
    • s=singlet,
    • d=doublet,
    • d.d=double doublet,
    • t=triplet,
    • m=multiplet,
    • sel=broad singlet.
    • Optical purity was analyzed by HPLC on a Chiralpak AD (250 mm×4.6) column eluted with a CO2/MeOH (80/20) mixture at 30° C. at a flow rate of 3 ml/min, P=20 MPa. The compounds were detected at 220 nm.
    • αD=rotatory power. The rotatory powers were determined using a Perkin-Elmer 241-MC polarimeter for the sodium D line (λ=589 nm); the concentrations were expressed as 10 mg/ml; the measurements were carried out at ambient temperature.
EXAMPLE 1 4-((S)-1-cyclopropylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide (Compound No 1) 1.1. Preparation of the tert-butyl ester of (R)-3-((methylsulphonyloxy)methyl)piperidine-1-carboxylic acid
2.16 ml of methanesulphonyl chloride followed by 3.86 ml of triethylamine were added to a solution of 5 g of the tert-butyl ester of (R)-3-(hydroxymethyl)piperidine-1-carboxylic acid in 80 ml of DCM cooled to 0° C. The medium was stirred for 1 h 30 minutes at 0° C. then 0.7 ml of triethylamine and 0.54 ml of methanesulphonyl chloride were added. After 30 minutes at 0° C., the medium was hydrolysed, the organic phase was washed twice with water then with a saturated NaCl solution and then dried over MgSO4. The medium was evaporated off to produce 6.8 g of a pale yellow oil.
1.2. Preparation of the tert-butyl ester of (S)-3-((4-benzylpiperazin-1-yl)methyl)piperidine-1-carboxylic acid
The unrefined product obtained in step 1.1 was dissolved in 75 ml of toluene. 12.16 g of benzylpiperazine were added, the reaction medium was sealed off and heated for 5 hours at 150° C. After returning to AT, the medium was diluted in an ether/pentane (1/1) mixture, washed twice with a saturated NaHCO3 solution, twice in water then with a saturated NaCl solution. After drying over MgSO4 and evaporating, the unrefined product was purified by silica gel flash chromatography to produce 5.73 g of the expected solid.
MH+=374.3 at t=5.26 min
1.3. Preparation of the tert-butyl ester of (S)-3-(piperazin-1-ylmethyl)piperidine-1-carboxylic acid
A solution of 4.0 g of the compound obtained in step 1.2 in 30 ml of methanol was hydrogenated in a closed reactor with microwave irradiation at 80° C. for 10 minutes in the presence of 1.7 g of Pd/C, 10% moisture, and 2.02 g of ammonium formate. The medium was filtered then evaporated to produce 2.89 g of a colourless oil.
1.4 Preparation of the tert-butyl ester of (S)-3-((4-(4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl)piperazin-1-yl)methyl)piperidine-1-carboxylic acid
2.59 g of DSC were added to a solution of 2.78 g of 4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-amine, a compound described in patent application WO2004/096798, in 7 ml of dichloromethane and the medium was stirred for 12 hours at AT. 2.59 g of the compound described in step 1.3 were added and the medium was stirred for 3 hours at AT. The medium was hydrolysed with a solution of saturated NaHCO3 then extracted into DCM. The organic phase was washed with water then with a saturated NaCl solution. After drying over MgSO4, the solution was concentrated and purified by silica gel flash chromatography to produce 4.0 g of the expected compound in the form of a white solid.
MH+=598.7 at t=8.26 min
1.5 Preparation of 4-((R)-1-piperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide
42 ml of a 4 M HCl solution in dioxane were added to a solution of 4 g of the compound obtained in step 1.4 in 10 ml of dioxane. The medium was stirred for 4 h at AT. The medium was filtered, the solid was rinsed with ether then taken up in DCM and treated with 1 M sodium hydroxide. The organic phase was washed with water then with a saturated NaCl solution. After drying over MgSO4, the solution was concentrated to produce 3.16 g of the desired compound.
MH+=498.7 at t=6.27 min
1.6 Preparation of 4-((S)-1-cyclopropylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide
0.35 g of (1-ethoxycyclopropoxy)trimethylsilane then 0.05 g of NaBH3CN and 0.24 g of acetic acid were added to a solution of 0.2 g of the compound described in step 1.5 in 5 ml of MeOH. The medium was stirred for 2 h at 60° C. The medium was concentrated then taken up in EtOAc. The organic phase was washed twice with a saturated NaHCO3 solution then with a saturated NaCl solution. After drying over MgSO4, the organic phase was concentrated then purified by flash chromatography to produce 0.16 g of the expected product.
MP=88° C.
αD=+4°(c=1, MeOH)
EXAMPLE 2 [4-(1-isopropylcarbamoylpiperidin-3-yl)piperazine-1-carboxylic acid 4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide (Compound No 2) 2.1. Preparation of the tert-butyl ester of 4-(1-benzylpiperidin-3-yl)piperazine-1-carboxylic acid
20 ml of a 10% sodium hydroxide solution were added to a suspension of 9.96 g of the hydrate of 1-benzylpiperidin-3-one mono-hydrochloride in suspension in 200 ml of DCM. The medium was stirred, the organic phase was decanted then washed with a saturated NaCl solution. After drying over MgSO4, the organic phase was concentrated. The gum obtained was taken up in 180 ml of DCE, 10.1 g of Boc-piperazine was added followed by 15.9 g of NaBH(OAc)3 and the medium was stirred for 12 h at AT. The medium was concentrated then taken up in EtOAc. The organic phase was washed twice with a saturated NaHCO3 solution then with a saturated NaCl solution. After drying over MgSO4, the organic phase was concentrated to produce 18.63 g of the expected product.
MP=103° C.
2.2. Preparation of 1-(1-benzylpiperidin-3-yl)piperazine
30 g of TFA were added to a solution of 9.2 g of the compound obtained in step 2.1 in 85 ml of DCM. The medium was stirred for 5 h then concentrated. The unrefined product obtained was taken up in DCM then washed 4 times with a 2 M sodium hydroxide solution. The organic phase was washed with a saturated NaCl solution. After drying over MgSO4, the organic phase was concentrated to produce 6.32 g of the expected product.
NMR 1H: δ (ppm)=7.28 (sel, 5H), 3.43 (sel, 2H), 2.88 (d, 1H), 2.70 (d, 1H), 2.64 (m, 4H), 2.43-2.22 (m, 5H), 1.85-1.58 (m, 4H), 1.39 (ddd, 1H), 1.15 (ddd, 1H).
2.3. Preparation of 4-(1-benzyl-piperidin-3-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide
The procedure was identical to that described in Example 1, starting from 4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-amine described in patent application WO2004/096798 and the compound obtained in step 2.2.
MP=90° C.
2.4. Preparation of 4-piperidin-3-ylpiperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide
1.26 g of chloroethylchloroformate were added to a solution of 1.69 g of the compound obtained in step 2.3 in 10 ml of DCE at 0° C. The medium was brought to AT then heated under reflux for 45 min. The medium was evaporated off then taken up in 10 ml of MeOH and heated for 1 h under reflux. The unrefined product was filtered, the solid was rinsed with ether then dried to produce 1.27 g of the expected compound in the form of a trihydrochloride.
MP=240° C.
MH+=484.7 at 6.81 min
2.5. Preparation of 4-(1-isopropylcarbamoylpiperidin-3-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide
0.06 ml of isopropyl isocyanate was added to a solution of 0.2 g of the compound obtained in step 2.4 in 1.2 ml of DCM, at 0° C. The medium was stirred for 2 h at 0° C. then hydrolysed with 5 ml of water and diluted with 10 ml of DCM. The organic phase was washed twice with a saturated NaHCO3 solution then with a saturated NaCl solution. After drying over MgSO4, the organic phase was concentrated then purified by flash chromatography to produce 0.16 g of the expected product.
MP=134° C.
MH+=568.7 at t=7.61 min
EXAMPLE 3 4-(1-cyclopropanesulphonylpiperidin-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide (Compound No 3) 3.1 Preparation of 4-(1-benzylpiperidin-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide
The procedure was identical to that described in Example 1, starting from 4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-amine, described in patent application WO2004/096798, and from 1-(1-benzylpiperidin-4-yl)piperazine.
MP=81° C.
3.2. Preparation of 4-piperidin-4-ylpiperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide
1.31 g of chloroethylchloroformate were added to a solution of 1.77 g of the compound obtained in step 3.1 in 10 ml of DCE, at 0° C. The medium was returned to AT then heated under reflux for 45 min. The medium was evaporated off then taken up in 10 ml of MeOH and heated for 1 h under reflux. The unrefined product was filtered, the solid was rinsed with ether then dried to produce 1.27 g of the expected compound in the form of a trihydrochloride.
MH+=484.6 at 6.21 min
3.3. Preparation of 4-(1-cyclopropanesulphonylpiperidin-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide
0.04 ml of cyclopropylsulphonyl chloride then 0.06 ml of triethylamine were added to a solution of 0.2 g of the compound described in preparation 3.2 in DCM. The medium was stirred at AT for 4 h. The medium was diluted in DCM then hydrolysed with 5 ml of water. The organic phase was washed twice with a saturated NaHCO3 solution then with a saturated NaCl solution. After drying over MgSO4, the organic phase was concentrated then purified by flash chromatography to produce 0.18 g of the expected product.
MP=138° C.
MH+=588.8 at t=7.49 min
EXAMPLE 4 Ethyl ester of 3-((R)-3-{4-[4-(5-cyclohexyl-2-methoxy-phenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)propionic acid (Compound No 4)
0.08 ml of triethylamine then 0.05 ml of the ethyl ester of 3-bromopropionic acid were added to a solution of 0.2 g of the compound described in step 1.5 in 2 ml of toluene. The medium was stirred for 48 h at AT. The medium was diluted in ethyl ether then filtered. The filtrate was washed with water then with a saturated NaCl solution. After drying over MgSO4, the organic phase was concentrated to produce 0.21 g of the expected product.
MH+=598.8 at t=6.84 min
EXAMPLE 5 3-((R)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)propionic acid (Compound No 5)
0.31 ml of 5 M sodium hydroxide was added to a solution of 0.208 g of the compound described in step 4 in 3 ml of methanol, at 0° C. The medium was stirred for 24 h at AT. The medium was concentrated then taken up in water. A 6N HCl solution was added dropwise until a precipitate appeared. The solid was extracted into DCM then, after drying over MgSO4, the organic phase was concentrated to produce 0.15 g of the expected product.
MH+=570.7 at t=6.64 min
MP=144° C.
EXAMPLE 6 4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide (Compound No 11)
This compound could be obtained using the process described in preparation 1.4 between 4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-amine and 1-(tetrahydro-2H-pyran-4-yl)piperazine described in J. Med. Chem.; EN; 47; 11; 2004; 2833-2838.
Synthesis may be carried out by another method:
6.1 Preparation of the tert-butyl ester of 4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazine-1-carboxylic acid
2.9 g of DSC were added to a solution of 3.0 g of 4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-amine, a compound described in patent application WO2004/096798, in 100 ml of dichloroethane; the medium was stirred for 16 hours at AT. 2.0 g of BOC-piperazine were added and the medium was stirred for 3 hours at AT. The medium was hydrolysed with a saturated NaHCO3 solution then extracted into DCM. The organic phase was washed with water then with a saturated NaCl solution. After drying over MgSO4, the solution was concentrated and purified by silica gel flash chromatography to produce 5.1 g of the expected compound in the form of a beige solid.
MH+=501.7 at t=11.72 min
6.2 Preparation of piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide
19 ml of a 4 M HCl solution in dioxane were added dropwise to a solution of 5.1 g of the compound obtained in step 6.1 in 100 ml of dioxane. The medium was stirred for 4 hours at AT. The medium was filtered, the solid was rinsed with ether then dried to produce 4.38 g of a white powder. The solid was taken up in DCM and treated with 1 M sodium hydroxide. The organic phase was washed with water then with a saturated NaCl solution. After drying over MgSO4, the solution was concentrated to produce 3.7 g of the expected compound.
MH+=401.6 at t=7.19 min
6.3 Preparation of 4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide
0.4 g of dihydro-2H-pyran-4(3H)-one then 1.59 g of NaBH(OAc)3 were added to a solution of 1.4 g of the piperazine obtained in step 6.2 in 13 ml of dichloroethane, and the medium was stirred for 72 hours at AT. The medium was concentrated then taken up in DCM. The organic phase was washed twice with a saturated NaHCO3 solution then with a saturated NaCl solution. After drying over MgSO4, the organic phase was concentrated to produce 1.7 g of the expected product.
The beige powder obtained was purified by silica gel flash chromatography to produce 1.42 g of the expected compound in the form of a white solid.
MH+=484.7 at t=7.42 min
MP=226° C.
EXAMPLE 7 4-(tetrahydropyran-4-carbonyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide (Compound No 13)
122 mg of TBTU, 26 mg of HOBt and 0.17 ml of DIPEA were added to a solution of 41 mg of tetrahydro-2H-pyran-4-carboxylic in 0.7 ml of DCM, at AT. The medium was stirred at AT for 1 hour 15 minutes then 100 mg of the compound described in step 6.2 were added. The medium was stirred for 12 hours at AT. The medium was taken up in DCM, washed three times in a saturated Na2CO3 solution then with a saturated NaCl solution. After drying over MgSO4 and evaporation, 0.21 g of the unrefined product was purified by silica gel flash chromatography to produce 0.08 g of the expected compound in the form of a white solid.
MH+=513.7 at t=9.88 min
MP=276° C.
EXAMPLE 8 4-(tetrahydropyran-4-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide (Compound No 17)
0.044 g of tetrahydro-2H-pyran-4-carbaldehyde was added to a solution of 0.155 g of the piperazine obtained in step 6.2 in 1.5 ml of dichloroethane followed, after stirring for 1 hour at AT, by 0.114 g of NaBH(OAc)3, and the medium was stirred for 12 hours at AT. The medium was diluted in DCM. The organic phase was washed twice with a saturated NaHCO3 solution then with a saturated NaCl solution. After drying over MgSO4, the organic phase was concentrated to produce 0.16 g of unrefined product. The solid was purified by silica gel flash chromatography to produce 0.12 g of the expected compound in the form of a white solid.
MH+=499.7 at t=7.75 min
MP=114° C.
EXAMPLE 9 4-((S)-1-carbamoylmethylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide (Compound No 14) 9.1 Preparation of the ethyl ester of ((S)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)acetic acid (Compound No 18)
This compound was synthesized starting from the compound described in preparation 1.5 and from ethyl 2-bromoacetate using an identical process to that described in preparation 4.
9.2 Preparation of ((S)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]-piperazin-1-ylmethyl}piperidin-1-yl)acetic acid (Compound No 15)
This compound was synthesized from the compound described in preparation 9.1 using an identical process to that described in preparation 5.
9.3 Preparation of 4-((S)-1-carbamoylmethylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide
0.1 g of TBTU, 0.02 g of HOBt then 0.08 ml of DIPEA were added to a solution of 0.1 g of the compound described in step 9.2 in 1 ml of DCM. After stirring for 2 hours at AT, ammonia was bubbled into the solution for 2 hours. The reaction medium was filtered, the filtrate was washed with a saturated NaHCO3 solution then with a saturated NaCl solution. After drying over MgSO4, the organic phase was concentrated to produce 0.09 g of unrefined product. The unrefined product was purified by silica gel flash chromatography to produce 0.052 g of the expected compound in the form of a white solid.
MH+=555.7 at t=6.68 min
MP=134° C.
EXAMPLE 10 4-[(S)-1-(2H-tetrazol-5-ylmethyl)piperidin-3-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide (Compound No 42) 10.1 Preparation of 4-((S)-1-cyanomethylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide (Compound No 26)
0.1 g of Na2CO3 was added to a solution of 0.45 g of the compound obtained in step 1.5 in 4 ml of acetone. The medium was cooled to 0° C., then 0.06 ml of 2-chloroacetonitrile was added and the medium was stirred until it reached AT. 0.012 ml of 2-chloroacetonitrile and 0.02 g of Na2CO3 were added. The medium was stirred for 2 hours at AT then concentrated. The unrefined product was comminuted in water then extracted with ether. The organic phase was washed twice with a saturated NaHCO3 solution then with a saturated NaCl solution. After drying over MgSO4, the organic phase was concentrated then purified by silica gel flash chromatography to produce 0.34 g of the expected compound in the form of a white solid.
MH+=537.7 at t=7.67 min
MP=106° C.
10.2 Preparation of 4-[(S)-1-(2H-tetrazol-5-ylmethyl)piperidin-3-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide
0.06 g of NaN3 and 0.14 g of ZnBr2 were added to a suspension of 0.34 g of the compound synthesized in step 10.1 in a mixture of 3 ml of water and 1 ml of isopropanol. The mixture was heated to 80° C. for 40 hours, 0.03 g of NaN3 and 0.07 g of ZnBr2 were then added and stirring was maintained at 80° C. for 12 hours. The medium was filtered, the solid was rinsed with water then with ether. The solid was purified by preparative HPLC to produce 56 mg of the expected compound.
MH+=580.7 at t=7.32 min
EXAMPLE 11 4-((S)-1-phenylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide (Compound No 30) 11.1 Preparation of (R)-1-benzyl-4-(piperidin-3-ylmethyl)piperazine
20 ml of a 4 M HCl solution in dioxane were added to a solution of 1.35 g of the compound obtained in step 1.2 in 5 ml of dioxane. The medium was stirred for 2 h at AT. The medium was filtered, the solid was rinsed with ether then taken up in DCM and treated with 1 M sodium hydroxide. The organic phase was washed with water then with a saturated NaCl solution. After drying over MgSO4, the solution was concentrated to produce 1 g of unrefined product.
MH+=274.3 at t=5.52 min
11.2 Preparation of (S)-1-benzyl-4-((1-phenylpiperidin-3-yl)methyl)piperazine
0.26 g of phenyl trifluoromethanesulphonate and 0.8 g of the amine prepared in step 11.1 in 5.6 ml of NMP were placed in a tube. The tube was heated under pressure in a microwave oven for 30 minutes at 230° C. After allowing to cool to AT, the medium was hydrolysed then extracted with ether. The organic phase was washed with water then with a saturated NaCl solution. After drying over MgSO4, the solution was concentrated to produce 0.41 g of unrefined product. The solid was purified by silica gel flash chromatography to produce 0.067 g of the expected compound.
MH+=350.3 at t=9.97 min
11.3 Preparation of (S)-1-((1-phenylpiperidin-3-yl)methyl)piperazine
0.05 g of 50% Pd/C, 10% moisture, was added to a solution of 0.066 g of the compound obtained in step 11.2 in 9 ml of methanol. The medium was stirred at AT for 48 hours under 10 bar of hydrogen. After filtering over celite, the filtrate was evaporated off to produce 0.037 g of the desired compound.
11.4 Preparation of 4-((S)-1-phenylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide
The procedure was identical to that described in Example 1, starting from 4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-amine, described in patent application WO2004/096798, and from the amine obtained in step 11.3.
MH+=574.8 at t=8.12 min
TABLE I
Figure US07825112-20101102-C00026
Compound
No R1 R2 R3 Y
 1 —OCH3
Figure US07825112-20101102-C00027
Figure US07825112-20101102-C00028
 		H
 2 —OCH3
Figure US07825112-20101102-C00029
Figure US07825112-20101102-C00030
 		H
 3 —OCH3
Figure US07825112-20101102-C00031
Figure US07825112-20101102-C00032
 		H
 4 —OCH3
Figure US07825112-20101102-C00033
Figure US07825112-20101102-C00034
 		H
 5 —OCH3
Figure US07825112-20101102-C00035
Figure US07825112-20101102-C00036
 		H
 6 —OCH3
Figure US07825112-20101102-C00037
Figure US07825112-20101102-C00038
 		H
 7 —OCH3
Figure US07825112-20101102-C00039
Figure US07825112-20101102-C00040
 		H
 8 —OCH3
Figure US07825112-20101102-C00041
Figure US07825112-20101102-C00042
 		H
 9 —OCH3
Figure US07825112-20101102-C00043
Figure US07825112-20101102-C00044
 		H
10 —OCH3
Figure US07825112-20101102-C00045
Figure US07825112-20101102-C00046
 		H
11 —OCH3
Figure US07825112-20101102-C00047
Figure US07825112-20101102-C00048
 		H
12 —OCH3
Figure US07825112-20101102-C00049
Figure US07825112-20101102-C00050
 		H
13 —OCH3
Figure US07825112-20101102-C00051
Figure US07825112-20101102-C00052
 		H
14 —OCH3
Figure US07825112-20101102-C00053
Figure US07825112-20101102-C00054
 		H
15 —OCH3
Figure US07825112-20101102-C00055
Figure US07825112-20101102-C00056
 		H
16 —OCH3
Figure US07825112-20101102-C00057
Figure US07825112-20101102-C00058
 		F
17 —OCH3
Figure US07825112-20101102-C00059
Figure US07825112-20101102-C00060
 		H
18 —OCH3
Figure US07825112-20101102-C00061
Figure US07825112-20101102-C00062
 		H
19 —OCH3
Figure US07825112-20101102-C00063
Figure US07825112-20101102-C00064
 		H
20 —OCH3
Figure US07825112-20101102-C00065
Figure US07825112-20101102-C00066
 		H
21 —OCH3
Figure US07825112-20101102-C00067
Figure US07825112-20101102-C00068
 		H
22 —OCH3
Figure US07825112-20101102-C00069
Figure US07825112-20101102-C00070
 		H
23 —OCH2—CH3 —(CH2)3—CH3
Figure US07825112-20101102-C00071
 		H
24 —OCH2—CH3
Figure US07825112-20101102-C00072
Figure US07825112-20101102-C00073
 		H
25 —OCH3 —(CH2)3—CH3
Figure US07825112-20101102-C00074
 		H
26 —OCH3
Figure US07825112-20101102-C00075
Figure US07825112-20101102-C00076
 		H
27 —OCH3
Figure US07825112-20101102-C00077
Figure US07825112-20101102-C00078
 		H
28 —OCH3
Figure US07825112-20101102-C00079
Figure US07825112-20101102-C00080
 		H
29 —OCH3
Figure US07825112-20101102-C00081
Figure US07825112-20101102-C00082
 		H
30 —OCH3
Figure US07825112-20101102-C00083
Figure US07825112-20101102-C00084
 		H
31 —OCH3
Figure US07825112-20101102-C00085
Figure US07825112-20101102-C00086
 		H
32 —OCH3
Figure US07825112-20101102-C00087
Figure US07825112-20101102-C00088
 		H
33 —OCH3
Figure US07825112-20101102-C00089
Figure US07825112-20101102-C00090
 		H
34 —OCH3
Figure US07825112-20101102-C00091
Figure US07825112-20101102-C00092
 		H
35 —OCH3
Figure US07825112-20101102-C00093
Figure US07825112-20101102-C00094
 		F
36 —OCH3
Figure US07825112-20101102-C00095
Figure US07825112-20101102-C00096
 		H
37 —OCH3
Figure US07825112-20101102-C00097
Figure US07825112-20101102-C00098
 		H
38 —OCH3
Figure US07825112-20101102-C00099
Figure US07825112-20101102-C00100
 		H
39 —OCH3
Figure US07825112-20101102-C00101
Figure US07825112-20101102-C00102
 		H
40 —OCH3
Figure US07825112-20101102-C00103
Figure US07825112-20101102-C00104
 		H
41 —OCH3
Figure US07825112-20101102-C00105
Figure US07825112-20101102-C00106
 		H
42 —OCH3
Figure US07825112-20101102-C00107
Figure US07825112-20101102-C00108
 		H
43 —OCH3
Figure US07825112-20101102-C00109
Figure US07825112-20101102-C00110
 		H
44 —OCH3
Figure US07825112-20101102-C00111
Figure US07825112-20101102-C00112
 		H
45 —OCH3
Figure US07825112-20101102-C00113
Figure US07825112-20101102-C00114
 		H
46 —OCH3
Figure US07825112-20101102-C00115
Figure US07825112-20101102-C00116
 		H
47 —OCH3
Figure US07825112-20101102-C00117
Figure US07825112-20101102-C00118
 		H
48 —OCH3
Figure US07825112-20101102-C00119
Figure US07825112-20101102-C00120
 		H
49 —OCH3
Figure US07825112-20101102-C00121
Figure US07825112-20101102-C00122
 		H
50 —OCH3
Figure US07825112-20101102-C00123
Figure US07825112-20101102-C00124
 		H
51 —OCH3
Figure US07825112-20101102-C00125
Figure US07825112-20101102-C00126
 		H
52 —OCH2—CH3
Figure US07825112-20101102-C00127
Figure US07825112-20101102-C00128
 		H
53 —OCH3
Figure US07825112-20101102-C00129
Figure US07825112-20101102-C00130
 		H
54 —OCH2—CH3 —(CH2)3—CH3
Figure US07825112-20101102-C00131
 		H
55 —OCH3
Figure US07825112-20101102-C00132
Figure US07825112-20101102-C00133
 		H
56 —OCH2—CH3
Figure US07825112-20101102-C00134
Figure US07825112-20101102-C00135
 		H
57 —OCH3
Figure US07825112-20101102-C00136
Figure US07825112-20101102-C00137
 		H
58 —OCH3 —(CH2)3—CH3
Figure US07825112-20101102-C00138
 		H
59 —OCH3 —O(CH2)2—CH3
Figure US07825112-20101102-C00139
 		H
60 —OCH3 —(CH2)2—CH3
Figure US07825112-20101102-C00140
 		H
61 —OCH3
Figure US07825112-20101102-C00141
Figure US07825112-20101102-C00142
 		H
Compound Synthesis Analytical
No p Salt pathway data Nomenclature
 1 2 — Example 1 MP = 88° C. 4-((S)-1-cyclopropylpiperidin-3-
αD = +4° (c = ylmethyl)piperazine-1-carboxylic acid [4-
1, MeOH) (5-cyclohexyl-2-methoxyphenyl)thiazol-
MH+ = 538.8 2-yl]amide
at t = 6.52 min
 2 2 — Example 2 MP = 134° C. 4-(1-isopropylcarbamoylpiperidin-3-
MH+ = 568.7 yl)piperazine-1-carboxylic acid [4-(5-
at t = 7.61 min cyclohexyl-2-methoxyphenyl)thiazol-2-
yl]amide
 3 2 — Example 3 MP = 138° C. 4-(1-cyclopropanesulphonylpiperidin-4-
MH+ = 588.8 yl)piperazine-1-carboxylic acid [4-(5-
at t = 7.49 min cyclohexyl-2-methoxyphenyl)thiazol-2-
yl]amide
 4 2 — Example 4 MH+ = 598.8 ethyl ester of 3-((R)-3-{4-[4-(5-
at t = 6.84 min cyclohexyl-2-methoxyphenyl)thiazol-2-
ylcarbamoyl]piperazin-1-
ylmethyl}piperidin-1-yl)propionic acid
 5 2 — Example 5 MP = 144° C. 3-((R)-3-{4-[4-(5-cyclohexyl-2-
MH+ = 570.7 methoxyphenyl)thiazol-2-
at t = 6.64 min ylcarbamoyl]piperazin-1-
ylmethyl}piperidin-1-yl)propionic acid
 6 2 — Example 4 MH+ = 612.8 ethyl ester of 4-((R)-3-{4-[4-(5-
at t = 6.62 min cyclohexyl-2-methoxyphenyl)thiazol-2-
ylcarbamoyl]piperazin-1-
ylmethyl}piperidin-1-yl)butyric acid
 7 2 — Example 5 MP = 136° C. 4-((R)-3-{4-[4-(5-cyclohexyl-2-
MH+ = 584.8 methoxyphenyl)thiazol-2-
at t = 6.74 min ylcarbamoyl]piperazin-1-
ylmethyl}piperidin-1-yl)butyric acid
 8 2 — Example 4 MH+ = 626.8 ethyl ester of 5-((R)-3-{4-[4-(5-
at t = 6.71 min cyclohexyl-2-methoxyphenyl)thiazol-2-
ylcarbamoyl]piperazin-1-
ylmethyl}piperidin-1-yl)pentanoic acid
 9 2 — Example 5 MP = 153° C. 5-((R)-3-{4-[4-(5-cyclohexyl-2-
MH+ = 598.8 methoxyphenyl)thiazol-2-
at t = 6.41 min ylcarbamoyl]piperazin-1-
ylmethyl}piperidin-1-yl)pentanoic acid
10 2 — Example 6 MP = 110° C. 4-cyclohexylpiperazine-1-carboxylic acid
MH+ = 483.7 [4-(5-cyclohexyl-2-
at t = 7.65 min methoxyphenyl)thiazol-2-yl]amide
11 2 — Example 6 MP = 226° C. 4-(tetrahydropyran-4-yl)piperazine-1-
MH+ = 485.7 carboxylic acid [4-(5-cyclohexyl-2-
at t = 7.42 min methoxyphenyl)thiazol-2-yl]amide
12 2 HCl Example 1 MH+ = 568.8 4-((S)-1-cyclopropylpiperidin-3-
at t = 7.61 min ylmethyl)piperazine-1-carboxylic acid [4-
(5-cyclohexyl-2-methoxyphenylthiazol-
2-yl]amide
13 2 — Example 7 MP = 276° C. 4-(tetrahydropyran-4-
MH+ = 513.7 carbonyl)piperazine-1-carboxylic acid [4-
at t = 9.88 min (5-cyclohexyl-2-methoxyphenyl)thiazol-
2-yl]amide
14 2 — Example 9 MP = 134° C. 4-((S)-1-carbamoylmethylpiperidin-3-
MH+ = 555.8 ylmethyl)piperazine-1-carboxylic acid [4-
at t = 6.57 min (5-cyclohexyl-2-methoxyphenyl)thiazol-
2-yl]amide
15 2 — Example 5 MP = 180° C. ((S)-3-{4-[4-(5-cyclohexyl-2-
MH+ = 556.7 methoxyphenyl)thiazol-2-
at t = 7.29 min ylcarbamoyl]piperazin-1-
ylmethyl}piperidin-1-yl)acetic acid
16 2 TFA Example 1 MP = 139° C. 4-((S)-1-cyclopropylpiperidin-3-
MH+ = 556.8 ylmethyl)piperazine-1-carboxylic acid [4-
at t = 7.02 min (5-cyclohexyl-2-methoxyphenyl)-5-
fluorothiazol-2-yl]amide
17 2 — Example 8 MP = 114° C. 4-(tetrahydropyran-4-
MH+ = 499.7 ylmethyl)piperazine-1-carboxylic acid [4-
at t = 7.75 min (5-cyclohexyl-2-methoxyphenyl)thiazol-
2-yl]amide
18 2 — Example 4 MP = 78° C. ethyl ester of ((S)-3-{4-[4-(5-cyclohexyl-
MH+ = 584.8 2-methoxyphenyl)thiazol-2-
at t = 7.06 min ylcarbamoyl]piperazin-1-
ylmethyl}piperidin-1-yl)acetic acid
19 2 — Example 10 MP = 88° C. 4-[(R)-1-(2-cyanoethyl)piperidin-3-
MH+ = 551.8 ylmethyl]piperazine-1-carboxylic acid [4-
at t = 5.66 min (5-cyclohexyl-2-methoxyphenyl)thiazol-
2-yl]amide
20 2 — Example 5 MH+ = 569.8 sodium salt of 3-((R)-3-{4-[4-(5-
at t = 6.99 min cyclohexyl-2-methoxyphenyl)thiazol-2-
ylcarbamoyl]piperazin-1-
ylmethyl}piperidin-1-yl)propionic acid
21 2 — Example 9 MH+ = 569.8 4-[(R)-1-(2-carbamoylethyl)piperidin-3-
at t = 6.66 min ylmethyl]piperazine-1-carboxylic acid [4-
(5-cyclohexyl-2-methoxyphenyl)thiazol-
2-yl]amide
22 2 — Example 1 MH+ = 552.8 4-((R)-1-cyclopropylpiperidine-3-
at t = 7.98 min carbonyl)piperazine-1-carboxylic acid [4-
(5-cyclohexyl-2-methoxyphenyl)thiazol-
2-yl]amide
23 2 — Example 1 MP = 86° C. 4-((S)-1-cyclopropylpiperidin-3-
MH+ = 526.8 ylmethyl)piperazine-1-carboxylic acid [4-
at t = 6.92 min (5-butyl-2-ethoxyphenyl)thiazol-2-
yl]amide
24 2 — Example 1 MP = 71° C. 4-((S)-1-cyclopropylpiperidin-3-
MH+ = 538.8 ylmethyl)piperazine-1-carboxylic acid [4-
at t = 6.92 min (5-cyclopentyl-2-ethoxyphenyl)thiazol-2-
yl]amide
25 2 — Example 1 MP = 89° C. 4-((S)-1-cyclopropylpiperidin-3-
MH+ = 512.7 ylmethyl)piperazine-1-carboxylic acid [4-
at t = 6.6 min (5-butyl-2-methoxyphenyl)thiazol-2-
yl]amide
26 2 — Example 6 MP = 106° C. 4-((S)-1-cyanomethylpiperidin-3-
MH+ = 537.7 ylmethyl)piperazine-1-carboxylic acid [4-
at t = 7.67 min (5-cyclohexyl-2-methoxyphenyl)thiazol-
2-yl]amide
27 2 — Example 1 MP = 141° C. 4-((R)-1-cyclopropylpiperidin-3-
MH+ = 524.7 yl)piperazine-1-carboxylic acid [4-
at t = 7.41 min (5-cyclohexyl-2-methoxyphenyl)thiazol-2-
yl]amide
28 2 — Example 1 MP = 106° C. 4-(1-cyclopropylpiperidin-4-
MH+ = 524.7 yl)piperazine-1-carboxylic acid [4-
at t = 6.59 min (5-cyclohexyl-2-methoxyphenyl)thiazol-2-
yl]amide
29 2 — Example 3 MP = 114° C. 4-((S)-1-cyclopropanesulphonylpiperidin-
MH+ = 602.8 3-ylmethyl)piperazine-1-carboxylic acid
at t = 7.8 min [4-(5-cyclohexyl-2-
methoxyphenyl)thiazol-2-yl]amide
30 2 — Example 11 MH+ = 574.8 4-((S)-1-phenylpiperidin-3-
at t = 8.12 min ylmethyl)piperazine-1-carboxylic acid [4-
(5-cyclohexyl-2-methoxyphenyl)thiazol-
2-yl]amide
31 2 — Example 3 MP = 210° C. 2-{4-[4-(5-cyclohexyl-2-
methoxyphenyl)thiazol-2-
ylcarbamoyl]piperazin-1-
ylmethyl}piperidine-1-sulphonic acid
32 2 — Example 8 MH+ = 542.8 4-[(S)-1-(2-hydroxyethyl)piperidin-3-
at t = 6.42 min ylmethyl]piperazine-1-carboxylic acid [4-
(5-cyclohexyl-2-methoxyphenyl)thiazol-
2-yl]amide
33 2 — Example 6 MP = 204° C. 4-(1,1-dioxohexahydro-1λ6-thiopyran-4-
MH+ = 533.7 yl)piperazine-1-carboxylic acid [4-(5-
at t = 7.65 min cyclohexyl-2-methoxyphenyl)thiazol-2-
yl]amide
34 2 — Example 3 MH+ = 594.7 4-[(S)-1-(2,2,-trifluoroacetyl)piperidin-3-
at t = 8.25 min ylmethyl]piperazine-1-carboxylic acid [4-
(5-cyclohexyl-2-methoxyphenyl)thiazol-
2-yl]amide
35 2 — Example 6 MH+ = 503.7 4-(tetrahydropyran-4-yl)piperazine-1-
at t = 7.61 min carboxylic acid [4-(5-cyclohexyl-2-
methoxyphenyl)-5-fluorothiazol-2-
yl]amide
36 2 — Example 6 MP = 207° C. 4-(4-hydroxycyclohexyl)piperazine-1-
MH+ = 499.7 carboxylic acid [4-(5-cyclohexyl-2-
at t = 7.29 min methoxyphenyl)-5-thiazol-2-yl]amide
37 2 — Example 2 MP = 145° C. 4-((S)-1-dimethylsulphamoylpiperidin-3-
MH+ = 605.8 ylmethyl]piperazine-1-carboxylic acid [4-
at t = (5-cyclohexyl-2-methoxyphenyl)thiazol-
11.78 min 2-yl]amide
38 2 — Example 6 MP = 166° C. 4-(1,2,2,6,6-pentamethylpiperidin-4-
MH+ = 554.8 yl)piperazine-1-carboxylic acid [4-
at t = 9.24 min (5-cyclohexyl-2-methoxyphenyl)thiazol-
2-yl]amide
39 2 — Example 6 MP = 189° C. 4-(2,2,6,6-tetramethylpiperidin-4-
MH+ = 540.8 yl)piperazine-1-carboxylic acid [4-
at t = 6.16 min (5-cyclohexyl-2-methoxyphenyl)thiazol-
2-yl]amide
40 2 — Example 8 MP = 98° C. 4-(2,2-dimethyltetrahydropyran-4-
MH+ = 527.7 ylmethyl)piperazine-1-carboxylic acid [4-
at t = 7.98 min (5-cyclohexyl-2-methoxyphenyl)thiazol-
2-yl]amide
41 2 — Example 6 MP = 118° C. 4-(tetrahydrothiopyran-4-yl)piperazine-1-
MH+ = 501.7 carboxylic acid [4-(5-cyclohexyl-2-
at t = 7.97 min methoxyphenyl)thiazol-2-yl]amide
42 2 — Example 10 MH+ = 580.7 4-[(S)-1-(2H-tetrazol-5-yl-
at t = 7.32 min methyl)piperidin-3-ylmethyl]piperazine-1-
carboxylic acid [4-(5-cyclohexyl-2-
methoxyphenyl)thiazol-2-yl]amide
43 2 TFA Example 3 MH+ = 690.3 4-[1-(5-chloro-1,3-dimethyl-1H-pyrazole-
at t = 1.78 min 4-sulphonyl)piperidin-2-
(method B) ylmethyl]piperazine-1-carboxylic acid [4-
(5-cyclohexyl-2-methoxyphenyl)thiazol-2-
yl]amide
44 2 TFA Example 3 MH+ = 656.3 4-[1-(1,3-dimethyl-1H-pyrazole-4-
at t = 1.70 min sulphonyl)piperidin-2-ylmethyl]piperazine-1-
(method B) carboxylic acid [4-(5-cyclohexyl-2-
methoxyphenyl)thiazol-2-yl]amide
45 2 TFA Example 3 MH+ = 656.3 4-[1-(1,5-dimethyl-1H-pyrazole-4-
at t = 1.71 min sulphonyl)piperidin-2-ylmethyl]piperazine-1-
(method B) carboxylic acid [4-(5-cyclohexyl-2-
methoxyphenyl)thiazol-2-yl]amide
46 2 TFA Example 3 MH+ = 642.3 4-[1-(1-methyl-1H-pyrazole-4-
at t = 1.68 min sulphonyl)piperidin-2-ylmethyl]piperazine-1-
(method B) carboxylic acid [4-(5-cyclohexyl-2-
methoxyphenyl)thiazol-2-yl]amide
47 2 TFA Example 3 MH+ = 643.3 4-[1-(5-methylisoxazole-4-
at t = 1.95 min sulphonyl)piperidin-2-ylmethyl]piperazine-1-
(method B) carboxylic acid [4-(5-cyclohexyl-2-
methoxyphenyl)thiazol-2-yl]amide
48 2 TFA Example 3 MH+ = 642.3 4-[1-(1-methyl-1H-pyrazole-4-
at t = 1.69 min sulphonyl)piperidin-2-ylmethyl]piperazine-1-
(method B) carboxylic acid [4-(5-cyclohexyl-2-
methoxyphenyl)thiazol-2-yl]amide
49 2 TFA Example 3 MH+ = 605.3 4-(1-dimethylsulphamoylpiperidin-2-
at t = 1.73 min ylmethyl)piperazine-1-carboxylic acid [4-
(method B) (5-cyclohexyl-2-methoxyphenyl)thiazol-2-
yl]amide
50 2 TFA Example 3 MH+ = 644.3 4-[1-(2,2,2-
at t = 1.80 min trifluoroethanesulphonyl)piperidin-2-
(method B) ylmethyl]piperazine-1-carboxylic acid [4-
(5-cyclohexyl-2-methoxyphenyl)thiazol-2-
yl]amide
51 2 — Example 3 MH+ = 668.3 4-[1-(4-methoxy-
at t = 1.83 min benzenesulphonyl)piperidin-2-
(method B) ylmethyl]piperazine-1-carboxylic acid [4-
(5-cyclohexyl-2-methoxyphenyl)thiazol-2-
yl]amide
52 2 — Example 6 MP = 190° C. 4-(tetrahydropyran-4-yl)piperazine-1-
MH+ = 485.7 carboxylic acid [4-(5-cyclopentyl-2-
at t = 10.3 min ethoxyphenyl)thiazol-2-yl]amide
53 2 TFA Example 3 MH+ = 657.3 4-[1-(3,5-dimethylisoxazole-4-
at t = 1.81 min sulphonyl)piperidin-2-ylmethyl]piperazine-
(method B) 1-carboxylic acid [4-(5-cyclohexyl-2-
methoxyphenyl)thiazol-2-yl]amide
54 2 — Example 6 MP = 171° C. 4-(tetrahydropyran-4-yl)piperazine-1-
MH+ = 473.7 carboxylic acid 4-(5-butyl-2-
at t = ethoxyphenyl)thiazol-2-yl]amide
10.92 min
55 2 — Example 3 MH+ = 642.8 4-[(S)-1-(1-methyl-1H-imidazole-4-
at t = 7.61 min sulphonyl)piperidin-3-ylmethyl]piperazine-
1-carboxylic acid [4-(5-cyclohexyl-2-
methoxyphenyl)thiazol-2-yl]amide
56 2 — Example 6 MH+ = 499.7 4-(tetrahydropyran-4-yl)piperazine-1-
at t = 7.63 min carboxylic acid [4-(5-cyclopentyl-2-
ethoxyphenyl)thiazol-2-yl]amide
57 2 — Example 6 MH+ = 471.6 4-(tetrahydropyran-4-yl)piperazine-1-
at t = 7.03 min carboxylic acid [4-(5-cyclopentyl-2-
methoxyphenyl)thiazol-2-yl]amide
58 2 — Example 6 MH+ = 459.6 4-(tetrahydropyran-4-yl)piperazine-1-
at t = 7.02 min carboxylic acid [4-(5-butyl-2-
methoxyphenyl)thiazol-2-yl]amide
59 2 — Example 6 MH+ = 461.6 4-(tetrahydropyran-4-yl)piperazine-1-
at t = 6.41 min carboxylic acid [4-(2-methoxy-5-
propoxyphenyl)thiazol-2-yl]amide
60 2 — Example 6 MH+ = 445.6 4-(tetrahydropyran-4-yl)piperazine-1-
at t = 6.64 min carboxylic acid [4-(5-propyl-2-
methoxyphenyl)thiazol-2-yl]amide
61 3 — Example 6 MH+ = 499.7 4-(tetrahydropyran-4-yl)[1,4]diazepane-1-
at t = 7.39 min carboxylic acid [4-(5-cyclohexyl-2-
methoxyphenyl)thiazol-2-yl]amide
The compounds according to the invention were used in pharmacological tests to determine the modulator effect thereof on the activity of chemokine receptors.
Chemokines are low molecular weight proteins which belong to the category of pro-inflammatory cytokines and are involved in the chemotactism of leukocytes and endothelial cells. Chemokines control a number of biological processes and are associated with inflammatory disorders appearing during stress conditions, with wounds or with infections; modulation of the effects of chemokines allows pathologies such as asthma, arthritis, allergies, auto-immune diseases, atherosclerosis or angiogenesis to be prevented or treated (C. D. Paavola et al., J. Biol. Chem., 1998, 273, (50), 33157-33165).
Chemokines include hMCP-1 (human monocyte chemotactic protein) which belongs to the CC chemokine group and is a natural agonist of the CCR2b receptor.
The inhibiting activity of the compounds according to the invention was measured on cells expressing the human CCR2b receptor. The concentration of natural hMCP-1 agonist which inhibited 50% (Cl50) of the activity of the CCR2b receptor was 0.57 nM. The compounds according to the invention had a Cl50 which was generally in the range 0.1 μM to 0.1 nM, preferably in the range 100 nM to 0.1 nM.
The following are brought into contact for 1 h 30 minutes at ambient temperature, in Millipore GF/B filter plates (ref. MAFBNOB 10 or 50): 50 μl of compound at 3×10−5 M in the reaction buffer or cold MCP-1 range ((R & D Systems). Recombinant human MCP-1) (final concentration of compound: 10−5 M), and 50 μl of iodinated MCP-1 ([125 l]-MCP-1 human recombinant Bolton+Hunter labelled (Amersham)) at 0.3 nM in distilled water (final concentration of iodinated MCP-1: 0.1 nM), and 50 μl of CHO-K1-CCR2B cells (obtained from Euroscreen Brussels, Belgium) at 6×105 cells/ml (final concentration in the reaction buffer: 3×105 cells/wells). The filters were saturated beforehand with 100 μl of PEI at a final concentration of 0.0125% in PBS, for 72 h at 4° C., and the PEI was removed by filtration. The content of the wells was filtered and washed twice with the reaction buffer, and the filters were left to dry overnight. The following day, 20 μl/well of “Wallac Optiphase Super Mix” scintillant were dispensed. The filters were impregnated for 1 to 2 h and then counted with Trilux Iodine 125 for 1 min.
Reaction buffer=PBS buffer, 50 nM Hepes, 1 mM CaCl2, 5 mM MgCl2, 0.5% fatty acid-free BSA, adjusted to pH 7.4.
As an example, compound No 9 had a Cl50 of 4 nM, compound No 10 had a Cl50 of 53 nM, compound No 22 had a Cl50 of 4 nM, compound No 40 had a Cl50 of 82 nM, compound No 41 had a Cl50 of 39 nM, compound No 33 had a Cl50 of 20 nM, compound No 11 had a Cl50 of 20 nM, compound No 23 had a Cl50 of 8 nM, compound No 29 had a Cl50 of 50 nM and compound No 45 had a Cl50 of 73 nM.
The compounds according to the invention can thus be used to prepare drugs, in particular drugs which are antagonists to the effect of chemokines.
In another aspect, then, the present invention pertains to drugs which comprise a compound of formula (I) or an addition salt thereof with a pharmaceutically acceptable acid, or a hydrate or a solvate.
Said drugs can be used in therapy, in particular in the prevention and treatment of various pathologies such as:
    • acute and chronic immuno-inflammatory diseases and syndromes such as atherosclerosis, restenosis, chronic pulmonary disease, in particular COPD (chronic obstructive pulmonary disease); respiratory distress syndrome; bronchial hyperactivity; colitis; silicosis; fibrous pathologies, pulmonary fibrosis, cystic fibrosis; viral or bacterial infections, AIDS, meningitis, malaria, leprosy, tuberculosis, herpes, cytomegalovirus infections; septic shock, septicaemia, endotoxic shock; graft rejection; bone pathologies such as osteoporosis, osteoarthritis; conjunctivitis; atypical or contact dermatitis; eczema; glomerulonephritis; pancreatitis; ulcerous colitis, auto-immune diseases such as rheumatoid polyarthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, lupus erythematosus, scleredema, psoriasis; Parkinson's disease; Alzheimer's disease; diabetes; cachexia; obesity;
    • the treatment of pain, in particular neuropathic and inflammatory pain;
    • allergic diseases such as allergic respiratory diseases, asthma, rhinitis, pulmonary hypersensitivity, retarded hypersensitivity;
    • diseases and disorders involving angiogenic processes, such as cancers (intratumoral angiogenesis), retinal disorders (age-related macular degeneracy: ARMD);
    • cardiac diseases: haemodynamic shock; cardiac ischemia; post-ischemic re-infusion seizures; myocardial infarctus; coronary thrombosis, cardiac insufficiency, angina pectoris.
In a further aspect, the present invention concerns pharmaceutical compositions comprising a compound according to the invention as the active principle. Said pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or a solvate of said compound, and at least one pharmaceutically acceptable excipient.
Selection of said excipients depends on the desired form of administration and pharmaceutical form, from the usual excipients which are known to the skilled person.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or any salt, solvate or hydrate thereof, may be administered in a unitary administration form, mixed with conventional pharmaceutical excipients, to animals and humans for prophylaxis or to treat the problems or diseases mentioned above.
Suitable unitary administration forms include oral forms such as tablets, soft or hard gelules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal or inhaled forms of administration, topical, transdermal, subcutaneous, intramuscular or intravenous forms of administration, rectal forms of administration and implants. For topical application, the compounds according to the invention may be used in creams, gels, pomades or lotions.
As an example, a unitary form of administration of a compound of the invention in the form of a tablet may comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Sodium croscaramellose 6.0 mg
Corn starch 15.0 mg
Hydroxypropyl-methylcellulose 2.25 mg
Magnesium stearate 3.0 mg.
Orally, the dose of active principle administered per day may be from 0.1 to 1000 mg/kg, in one or more doses.
Particular cases may arise in which higher or lower doses are appropriate: such doses do not fall within the scope of the invention. Usually, the appropriate dose for each patient is determined by the physician as a function of the mode of administration and the patient's weight and response.
In a still further aspect, the present invention also concerns a method for treating the disorders indicated above, which comprises administering an effective dose of a compound according the invention, or one of its pharmaceutically acceptable salts or hydrates or solvates, to a patient.

Claims (17)

1. A compound of formula (I):
Figure US07825112-20101102-C00143
wherein:
R1 represents a hydrogen atom, a halogen atom, a (C1-C8)alkyl, trifluoro(C1-C4)alkyl, —OH, —O—(C1-C8)alkyl, —O—trifluoro(C1-C8)alkyl, —O—(C1-C8)alkyl-(C3-C10)cycloalkyl, —O—(C3-C10)cycloalkyl, —O—CH2—CH═CH2 or —S—(C1-C4)alkyl group;
R2 represents a hydrogen atom, a halogen atom, an —OH, (C1-C8)alkyl, trifluoro(C1-C4)alkyl, perfluoro(C1-C4)alkyl, (C3-C10)cycloalkyl, —O—(C1-C8)alkyl, —O—(C1-C8)alkyl(C3-C10)cycloalkyl, —O—(C3-C10)cycloalkyl, —O—CH2—CH═CH2 or —(C1-C8)alkyl(C3-C8)cycloalkyl group;
Y represents a hydrogen atom or a halogen atom;
p represents 2 or 3;
R3 represents:
a1) a group of formula —(CH2)a-A in which a represents 1, 2, 3 or 4, and A is selected from the group consisting of:
Figure US07825112-20101102-C00144
in which R7 is selected from the group consisting of:
—(C1-C8)alkyl-COO—(C1-C8)alkyl,
—(C3-C6)cycloalkyl,
-COO—(C3-C6)cycloalkyl,
—CO—NH((C1-C5)alkyl),
—(C1-C8)alkyl-CN,
—(C1-C8)alkylimidazole,
—(C1-C8)alkyl-COOH,
—(C1-C8)alkyl-CO—NH2,
—(C1-C8)alkyl-CO—NH((C1-C5)alkyl,
—(C1-C8)alkyl-CO—NH((C3-C6)cycloalkyl),
—(C1-C8)alkyl-CO—N((C1-C5)alkyl)((C3-C6)cycloalkyl),
—(C1-C8)alkyl-CO—N((C1-C5)alkyl)2, and
—(C1-C8)alkyl-CO—N((C3-C6)cycloalkyl)2;
and when two alkyl or cycloalkyl substituents are bonded to the nitrogen atom, they may be independently identical or different;
a2) a group of formula -CO(CH2)b-A in which b represents 0, 1, 2, 3 or 4, and A is selected from the group consisting of:
Figure US07825112-20101102-C00145
in which R7 is as defined above;
a3) a group —B in which B is selected from the group consisting of:
Figure US07825112-20101102-C00146
in which R7 is as defined above;
or an acid addition salt thereof.
2. A compound according to claim 1, of formula (I.a):
Figure US07825112-20101102-C00147
in which R1, R2, R3 and Y are as defined in claim 1;
or an acid addition salt thereof.
3. A compound according to claim 2, of formula (I.a) wherein R1 is in the 2-position and R2 is in the 5-position;
or an acid addition salt thereof
4. A compound according to claim 1, wherein R1 represents —O—(C1-C8)alkyl;
or an acid addition salt thereof.
5. A compound according to claim 1, wherein R2 represents a (C1-C8)alkyl, (C3-C10)cycloalkyl, perfluoro(C1-C4)alkyl or —O—(C1-C8)alkyl group;
or an acid addition salt thereof.
6. A compound according to claim 5, wherein R2 represents a (C1-C8)alkyl, (C3-C10)cycloalkyl or —O—(C1-C8)alkyl group;
or an acid addition salt thereof.
7. A compound according to claim 1, wherein R3 represents a group of formula —(CH2)a-A in which a represents 1, 2, 3 or 4, and A is selected from the group consisting of:
Figure US07825112-20101102-C00148
in which R7 is as defined in claim 1;
or an acid addition salt thereof.
8. A compound according to claim 7, wherein A is selected from the group consisting of:
Figure US07825112-20101102-C00149
or an acid addition salt thereof.
9. A compound according to claim 1, wherein R3 represents a group of formula —CO(CH2)b-A in which b represents 0, 1, 2, 3 or 4, and A is selected from the group consisting of:
Figure US07825112-20101102-C00150
in which R7 is as defined in claim 1;
or an acid addition salt thereof.
10. A compound according to claim 9, wherein A is selected from the group consisting of:
Figure US07825112-20101102-C00151
or an acid addition salt thereof.
11. A compound according to claim 1, wherein R3 represents a group —B in which B is selected from the group consisting of:
Figure US07825112-20101102-C00152
in which R7 is as defined in claim 1;
or an acid addition salt thereof.
12. A compound according to claim 1, wherein R7 is selected from the group consisting of:
—(C1-C8)alkyl-COO—(C1-C5)alkyl,
—(C3-C6)cycloalkyl,
—CO—NH((C1-C5)alkyl),
—(C1-C8)alkyl-CN,
—(C1-C8)alkyl-COOH, and
—(C1-C8)alkyl-CO—NH2,
and when two alkyl or cycloalkyl substituents are bonded to a nitrogen atom, they may be independently identical or different;
or an acid addition salt thereof.
13. A compound according to claim 1, selected from the group consisting of:
4-((S)-1-cyclopropylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
4-(1-isopropylcarbamoylpiperidin-3-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
the ethyl ester of 3-((R)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)propionic acid;
3-((R)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)propionic acid;
the ethyl ester of 4-((R)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)butyric acid;
4-((R)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)butyric acid;
the ethyl ester of 5-((R)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)pentanoic acid;
5-((R)-3-{4-[4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)pentanoic acid;
4-cyclohexylpiperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide; and
4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexyl-2-methoxyphenyl)thiazol-2-yl]amide;
or an acid addition salt, hydrate or solvate thereof.
14. A compound which is:
4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
or a pharmaceutically acceptable salt thereof.
15. A compound according to claim 1, selected from the group consisting of:
4-((S)-1-cyclopropylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
4-(tetrahydropyran-4-carbonyl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
4-((S)-1-carbamoylmethylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
((S)-3-{4-[4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)acetic acid;
4-((S)-1-cyclopropylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenl)-5-fluorothiazol-2-yl]amide;
4-(tetrahydropyran-4-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
the ethyl ester of ((S)-3-{4-[4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-ylcarbamoyl]piperazin-1-ylmethyl}piperidin-1-yl)acetic acid;
4-[(R)-1-(2-cyanoethyl)piperidin-3-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexl -2-methoxyphenyl)thiazol-2-yl]amide;
4-[(R)-1-(2-carbamoylethyl)piperidin-3-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
4-((R)-1-cyclopropylpiperidine-3-carbonyl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
4-((S)-1-cyclopropylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-butyl-2-ethoxyphenyl)thiazol-2-yl]amide;
4-((S)-1-cyclopropylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclopentl-2-ethoxyphenyl)thiazol-2-yl]amide;
4-((S)-1-cyclopropylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-butyl-2-methoxyphenyl)thiazol-2-yl]amide;
4-((S)-1-cyanomethylpiperidin-3-ylmethyl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
4-((R)-1-cyclopropylpiperidin-3-yl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
4-(1-cyclopropylpiperidin-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenl)-5-fluorothiazol-2-yl]amide;
4-[1-(1-methyl-1H-imidazole-4-sulphonyl)piperidin-2-ylmethyl]piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclopentl-2-ethoxyphenyl)thiazol-2-yl]amide;
4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-butyl-2-ethoxyphenyl)thiazol-2-yl]amide;
4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-3ethoxyphenyl)thiazol-2-yl]amide;
4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclopentl-2-methoxyphenyl)thiazol-2-yl]amide;
4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-butyl-2-methoxyphenyl)thiazol-2-yl]amide;
4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(2-methoxy-5-propoxyphenyl)thiazol-2-yl]amide;
4-(tetrahydropyran-4-yl)piperazine-1-carboxylic acid [4-(5-propyl-2-methoxyphenyl)thiazol -2-yl]amide; and
4-(tetrahydropyran-4-yl)[1,4]diazepane-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
or an acid addition salt thereof.
16. A compound selected from the group consisting of:
4-(1,1-dioxohexahydro-1λ6-thiopyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
4-(4-hydroxycyclohexyl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
4-(1,2,2,6,6-pentamethylpiperidin-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
4-(2,2,6,6-tetramethylpiperidin-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide;
4-(2,2-dimethyltetrahydropyran-4-ylmethyl)piperazine-1-carboxylic acid [445-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide; and
4-(tetrahydrothiopyran-4-yl)piperazine-1-carboxylic acid [4-(5-cyclohexl-2-methoxyphenyl)thiazol-2-yl]amide.
17. A pharmaceutical composition comprising a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt of said compound, as well as at least one pharmaceutically acceptable excipient.
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